Heteroaryl-substituted carboxamides and their use as pharmaceuticals

ABSTRACT

The present invention relates to heteroaryl-substituted carboxamides of the formula I, 
     
       
         
         
             
             
         
       
     
     in which Het, A, X, R 1 , R 2  and R 3  have the meanings indicated in the claims, which modulate the transcription of endothelial nitric oxide (NO) synthase and are valuable pharmacologically active compounds. Specifically, the compounds of the formula I upregulate the expression of the enzyme endothelial NO synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired. The invention further relates to processes for the preparation of compounds of the formula I, to pharmaceutical compositions comprising them, and to the use of compounds of the formula I for the manufacture of a medicament for the stimulation of the expression of endothelial NO synthase or for the treatment of various diseases including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency, for example.

FIELD OF THE INVENTION

The present invention relates to heteroaryl-substituted carboxamides of the formula I,

in which Het, A, X, R¹, R² and R³ have the meanings indicated below, which modulate the transcription of endothelial nitric oxide (NO) synthase and are valuable pharmacologically active compounds. Specifically, the compounds of the formula I upregulate the expression of the enzyme endothelial NO synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired. The invention further relates to processes for the preparation of compounds of the formula I, to pharmaceutical compositions comprising them, and to the use of compounds of the formula I for the manufacture of a medicament for the stimulation of the expression of endothelial NO synthase or for the treatment of various diseases including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency, for example.

BACKGROUND OF THE INVENTION

Endothelial NO synthase (eNOS, NOS-III) belongs to a group of three isoenzymes which produce nitric oxide (nitrogen monoxide, NO) by oxidation of arginine. Endothelially released NO is of central importance in a number of key cardiovascular mechanisms. It has a vasodilating effect and inhibits the aggregation of platelets, the adhesion of leukocytes to the endothelium and the proliferation of intimal smooth muscle cells.

Endothelial NO synthase is subject to physiological and pathophysiological regulation both at the transcriptional and at the post-transcriptional level. Enzyme already present in the endothelium may undergo calcium-dependent and calcium-independent activation through phosphorylation of specific amino acids, but also by direct interactions with specific proteins. Stimulators of this, usually transient, NO release are extracellular arginine, 17β-estrogen and the mechanical stimulus exerted on the luminal surface of the endothelium by the blood flow (shear stress). The latter additionally leads to regulation of eNOS at the transcriptional level. Thus, for example, Sessa et al. (Circ. Research 74 (1994) 349) were able to obtain a marked increase in eNOS by means of exercise training and the increase in shear stress associated therewith.

Whether regulation at the post-transcriptional level is relevant in vivo, has not been unambiguously proven. Thus, for example, administration of a high arginine dose is followed by only a transient improvement in the endothelium-dependent vasorelaxation in patients with coronary heart disease.

On the other hand, the significance of the upregulation of the eNOS protein is scientifically accepted. Thus, there are findings which show that the protective properties of the HMG-CoA reductase inhibitor simvastatin can be attributed, besides to the lipid lowering, also in part to an increase in eNOS expression in vivo (Endres et al., Proc. Natl. Acad. Sci. USA 95 (1998) 8880). It is additionally known that single point mutations in the 5′-flanking region of the eNOS gene (“eNOS promoter”), and the reduction in the rate of eNOS gene transcription associated therewith, in the Japanese population is associated with an increase in the risk of coronary spasms (Nakayama et al., Circulation 99 (1999) 2864).

The current assumption therefore is that the transcriptional and post-transcriptional mechanisms of eNOS regulation are seriously disturbed in a large number of disorders, especially in cardiovascular disorders. Even in very early stages of a wide variety of cardiovascular disorders it is possible for a dysfunction of this type in the endothelium lining the blood vessels to lead to a deficiency of bioactive NO, which is manifested as the disorder progresses in the form of measurable pathophysiological and morphological changes. Thus, critical steps in early atherogenesis are speeded up by a decrease in endothelial NO release, such as, for example, the oxidation of low density lipoproteins, the recruitment and deposition of monocytes in the intima of vessels, and the proliferation of intimal cells. A consequence of atherogenesis is the formation of plaques on the inside of the blood vessels, which may in turn lead, through a diminution in the shear stress, to a further decrease in endothelial NO release and a further deterioration in the pathology. Since endothelial NO is also a vasodilator, a decrease thereof frequently also leads to hypertension which may, as an independent risk factor, cause further organ damage.

The aim of a therapeutic approach to the treatment of these disorders must accordingly be to interrupt this chain of events by increasing the endothelial NO expression. Gene transfer experiments which lead in vitro to overexpression of NO synthase in previously damaged vessels are in fact able to counteract the described processes and are thus evidence of the correctness of this approach (Varenne et al., Hum. Gene Ther. 11 (2000) 1329).

Some low molecular weight compounds which, in cell cultures, may lead to a direct effect on eNOS transcription and expression are disclosed in the literature. For the statins, as has already been mentioned, it has been possible to show such an increase in eNOS in vivo as a side effect. In view of the known range of side effects of this class of substances, however, it is unclear how far use of this effect can be made in a toxicologically unproblematic dose. Liao et al. claim in WO 99/47153 and WO 00/03746 the use of rhoGTPase inhibitors and agents which influence the organization of the actin cytoskeleton for increasing eNOS in endothelial cells and for the therapy of various disorders such as, for example, strokes or pulmonary hypertension without, however, indicating a specific way of achieving this. Certain amide derivatives which upregulate the expression of endothelial NO synthase, in particular N-cycloalkyl amides in which the cycloalkyl ring is fused to a benzene ring or a heteroaromatic ring, have been described in WO 02/064146, WO 02/064545, WO 02/064546, WO 02/064565, WO 2004/014369, WO 2004/014372 and WO 2004/014842. Certain triaza- and tetraaza-anthracenedione derivatives which upregulate the expression of endothelial NO synthase have been described in WO 2004/094425. There still exists a need for further compounds which upregulate the expression of endothelial NO synthase and have a favorable property profile and are useful as pharmaceuticals for the treatment of various diseases such as atherosclerosis, coronary artery disease or cardiac insufficiency, for example. Surprisingly it has now been found that the compounds of the formula I are modulators of the transcription of endothelial NO synthase and in particular stimulate, or upregulate, the expression of eNOS, and are useful for the treatment of various diseases such as the mentioned cardiovascular disorders.

Certain heteroaryl-substituted carboxamides, in which an aryl or heteroaryl group is linked to the heteroaryl substituent and which are structurally related to formula I, have already been described. For example, in EP 0382199 and EP 0440183 oxazole compounds are described which are useful for the treatment of diabetes and metabolic disorders and the definition of which comprises, among others, 3-(oxazol-2-yl)-propionamides and 4-(oxazol-2-yl)-butyramides which carry an optionally substituted phenyl group in the 4-position of the oxazole ring and optionally an alkyl group in the 5-position of the oxazole ring. In EP 0432740 anti-inflammatory 2-substituted thiazole derivatives are described which are characterized by a 3-alkyl-5-tert-butyl-4-hydroxyphenyl substituent in the 4-position and in which the substituent in the 2-position can be, among others, a carboxamide group which is linked to the thiazole ring by an alkanediyl group the chain of which can optionally contain an oxygen atom, a sulfur atom or a carbonyl group. In EP 0018497 and U.S. Pat. No. 4,645,525 herbicidal 2-azolyloxy-acetamides and 2-alkyl-2-azolyloxy-acetamides are described in which the 5-membered azole ring comprises at least one nitrogen ring member and one ring member chosen from oxygen and sulfur and can be substituted by various substituents including optionally substituted aryl, arylalkyl-, aryloxy, arylthio, for example. Certain imidazol-2-yl compounds, which are inhibitors of acyl CoA cholesterol acyl transferase useful for the treatment of hypercholesterolemia and atherosclerosis and which in particular are substituted by two phenyl groups in positions 4 and 5 of the imidazole ring, are described in EP 0372445 and U.S. Pat. No. 5,358,946. Some 3-(4,5-diphenyl-imidazol-2-ylthio)-propionamides are also described in Ali et al., J. Prakt. Chem. 316 (1974) 147. Certain thiazol-2-yl compounds, which have 5-lipoxygenase inhibitory and antithrombotic activity and are substituted by two phenyl groups in positions 4 and 5 of the thiazole ring, such as 4,5-disubstituted 2-(ureidomethyl)-thiazoles, are described in EP 0388909. In EP 0417751 2-guanidino-thiazol-4-yl-substituted thiazoles and pyridines are described which are H₂ receptor antagonists useful for the treatment of ulcers and which can contain, among other groups, a urea moiety which is linked to the thiazole or pyridine ring by an alkanediyl group. In WO 96/16040 and US 2003/0018025, which relate to brain dopamine agonistic and antagonistic imidazolylalkylamine derivatives, certain 1-(2-(4-phenylimidazol-4(5)-yl)propanoyl)-piperazines and -piperidines are described as intermediates which comprise a phenyl or heteroaryl group in the piperazine group and the piperidine group and which can be reduced to the respective imidazolylalkylamine derivatives. The generic definition of the compounds in WO 00/45635, which relates to antimicrobial thiazole derivatives and combinatorial libraries thereof, comprises 2-(thiazol-2-ylamino)acetamides in which the thiazole ring can carry phenyl and heteroaryl substituents. Certain cannabinoid CB1 receptor antagonistic thiophen-2-ylmethylamine derivatives in which the amino group can be part of a urea moiety, which carry in positions 4 and 5 of the thiophene ring two optionally substituted phenyl groups and therefore are not comprised by the definition of the compounds of the present invention, are described in WO 2006/084975. Some further specific heteroaryl-substituted carboxamides in which an optionally substituted phenyl group is linked to the heteroaryl substituent which is a 5-membered pyrrolyl, imidazolyl or thiazolyl group, are known, such as the compound N-(4-chloro-phenyl)-2-(4-phenyl-1H-imidazol-2-ylsulfanyl)-acetamide, for example, which may also be named as N-(4-chloro-phenyl)-2-(4-phenyl-1H-imidazol-2-ylthio)-acetamide or in its tautomeric form as N-(4-chloro-phenyl)-2-(5-phenyl-1H-imidazol-2-ylsulfanyl)-acetamide and which is described in Ivanova et al., Chemistry of Heterocyclic Compounds 41 (2005) 761. A stimulating effect of known heteroaryl-substituted carboxamides on the transcription or the expression of eNOS and their use in the treatment of diseases which is based on such effect, has not been described.

SUMMARY OF THE INVENTION

A subject of the present invention is a compound of the formula I,

in which A is chosen from CH₂—CH₂, CH₂—CH₂—CH₂, Y—CH₂, CH₂—Y, Y—CH₂—CH₂ and CH₂—CH₂—Y, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ or Y—CH₂—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond, CH₂, O and NH, provided that X cannot be O or NH if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from (C₁-C₄)-alkyl and fluorine; R^(b) is chosen from hydrogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-CO—; R¹ and R² are independently of each other chosen from hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, but cannot simultaneously be hydrogen, wherein the groups (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₆)-alkenyl and (C₃-C₆)-alkynyl can all be substituted by one or more identical or different substituents R⁶, and the groups C_(n)H_(2n) can all be substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl, and all phenyl and heteroaryl groups can independently of each other be substituted on carbon atoms by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring members chosen from N, NR⁹, O, S, SO and SO₂ which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted on ring carbon atoms by one or more identical or different substituents R⁸; R³ is chosen from phenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, H₂NSO₂— and (C₁-C₄)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁶ is chosen from fluorine, OH, oxo, (C₁-C₄)-alkyloxy, (C₁-C₄)-alkylmercapto, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁷ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, SF₅, H₂NSO₂— and (C₁-C₄)-alkyl-SO₂—; R⁸ is chosen from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, oxo, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁹ is chosen from hydrogen, (C₁-C₄)-alkyl, ((C₁-C₄)-alkyl)-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, CF₃ and (C₁-C₄)-alkyloxy; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered or 6-membered, monocyclic aromatic group which contains one, two or three identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; n is 0, 1 or 2, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof; provided that the group R³—X-Het cannot be 4-phenyl-thiazol-2-yl if simultaneously the group A-CO—NR¹R² is the group O—CH₂—CO—N(CH₃)-phenyl, the group S—CH₂—CO—NH—CH₂—CH₂—OH, the group CH₂—NH—CO—NH-phenyl, the group NH—CH₂—CO—N(CH₃)₂, or the group NH—CH₂—CO—NH—R⁹⁰ in which R⁹⁰ is phenyl, 3-chloro-phenyl, 4-chloro-phenyl or 3-chloro-4-fluoro-phenyl; and provided that the group R³—X-Het cannot be 4-(4-chloro-phenyl)-thiazol-2-yl if simultaneously the group A-CO—NR¹R² is the group S—CH₂—CO—NH—R⁹¹ in which R⁹¹ is phenyl, 4-bromo-phenyl, 4-chloro-phenyl, 4-methoxy-phenyl or 4-methyl-phenyl; and provided that the group R³—X-Het cannot be 3-phenyl-isoxazol-5-yl, 3-ethyl-4-phenyl-isoxazol-5-yl, 5-phenyl-isoxazol-3-yl or 4-chloro-5-(3,4-dichloro-phenyl)-thiazol-2-yl if simultaneously the group A-CO—NR¹R² is the group O—CH₂—CO—N(CH₃)— phenyl; and provided that the group R³—X-Het cannot be a pyrrol-2-yl group which is substituted by ethoxycarbonyl in the 3-position and by phenyl, 4-chloro-phenyl or 4-bromophenyl in the 4-position, if simultaneously the group A-CO—NR¹R² is the group S—CH₂—CO—NH—R⁹² in which R⁹² is benzyl, 3,4-dimethoxy-benzyl or 2-(4-methoxy-phenyl)-ethyl; and provided that the compound of the formula I cannot be N-benzyl-3-[4-(4-chloro-phenyl)-oxazol-2-yl]-N-methyl-propionamide, 3-[4-(4-chloro-phenyl)-oxazol-2-yl]-N-methyl-propionamide, N,N-diethyl-3-[4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-thiazol-2-yl]-propionamide, 2-(4-chloro-5-phenyl-thiazol-2-yloxy)-1-(2-methyl-piperidin-1-yl)-ethanone, (4-methyl-phenyl)-carbamic acid 4-(3-amino-4-methoxy-phenyl)-thiazol-2-ylmethyl ester or N-(4-chloro-phenyl)-2-(4-phenyl-1H-imidazol-2-ylsulfanyl)-acetamide.

Another subject of the present invention is the use of a compound of the formula Ia

in which A is chosen from CH₂—CH₂, CH₂—CH₂—CH₂, Y—CH₂, CH₂—Y, Y—CH₂—CH₂ and CH₂—CH₂—Y, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ or Y—CH₂—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is 5-membered to 10-membered, monocyclic or bicyclic, aromatic group which contains one or more identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond, CH₂, O, CH₂—O, O—CH₂, S, NH and N((C₁-C₄)-alkyl), or X is absent and in this case the phenyl, naphthalenyl or heteroaryl group representing the group R³ is fused to the group Het, provided that X cannot be O, CH₂—O, S, NH or N((C₁-C₄)-alkyl) if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from (C₁-C₆)-alkyl, fluorine and oxo; R^(b) is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₆)-alkyl, CF₃ and (C₁-C₆)-alkyloxy; R¹ and R² are independently of each other chosen from hydrogen, (C₁-C₁₀)-alkyl, (C₃-C₁₀)-alkenyl, (C₃-C₁₀)-alkynyl, (C₃-C₁₀)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)—, naphthalenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, wherein the groups (C₁-C₁₀)-alkyl, (C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-alkenyl and (C₃-C₁₀)-alkynyl can all be substituted by one or more identical or different substituents R⁶, and the groups C_(n)H_(2n) can all be substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl, and all phenyl, naphthalenyl and heteroaryl groups can independently of each other be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring members chosen from N, NR⁹, O, S, SO and SO₂ which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸; R³ is chosen from phenyl, naphthalenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, COOH, CONH₂, CN, CF₃, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂—, H₂NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, COOH, CONH₂, CN, CF₃, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁶ is chosen from fluorine, OH, oxo, (C₁-C₆)-alkyloxy, (C₁-C₆)-alkylmercapto, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁷ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, SF₅, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁸ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, oxo, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁹ is chosen from hydrogen, (C₁-C₆)-alkyl, ((C₁-C₆)-alkyl)-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, CF₃ and (C₁-C₄)-alkyloxy; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered to 10-membered, monocyclic or bicyclic aromatic group which contains one or more identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; n is 0, 1, 2 or 3, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the stimulation of the expression of endothelial NO synthase and for the treatment of a disease in which such a stimulation, or an increase in NO level, is desired, for example a cardiovascular disorder such as atherosclerosis, coronary artery disease or cardiac insufficiency or any other disease mentioned above or below herein.

DETAILED DESCRIPTION OF THE INVENTION

If in the compounds of the formulae I and Ia any groups, substituents, heteroatom ring members, numbers or other features such as, for example, R^(a), R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, alkyl groups, the number n, etc. can occur several times, they can all independently of one another have any of the indicated meanings and can in each case be identical or different from one another. Similarly, in groups such as dialkylamino, for example, the alkyl groups can be identical or different.

Alkyl, alkenyl and alkynyl groups can be linear, i.e. straight-chain, or branched. This also applies when they are part of other groups, for example alkyloxy groups (=alkoxy groups, i.e. alkyl-O— groups), alkyloxycarbonyl groups or alkyl-substituted amino groups, or when they are substituted. Substituted alkyl, alkenyl and alkynyl groups can be substituted by one or more, for example one, two, three, four or five, identical or different substituents which can be located in any desired positions.

Examples of alkyl groups containing one, two, three, four, five, six, seven, eight, nine or ten carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl and, more specifically, the n-isomer of each of these groups, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl or 3,3-dimethylbutyl. Alkenyl groups and alkynyl groups containing three, four, five, six, seven, eight, nine or ten carbon atoms can contain one or more double bonds and/or triple bonds. Preferably they contain one double bond or one triple bond, respectively, which can be present in any desired position of the group. In one embodiment of the invention a carbon atom which is part of a double bond or triple bond is not directly bonded to a nitrogen atom. I.e., in this embodiment a double bond or triple bond is not present in the terminal position of the alkenyl or alkynyl group which is directly bonded to the nitrogen atom. Examples of alkenyl and alkynyl are prop-1-enyl, prop-2-enyl (=allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, 4-methylhex-4-enyl, dec-3-enyl, dec-9-enyl, prop-2-ynyl (=propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl or hex-5-ynyl.

As far as applicable, the preceding explanations regarding alkyl groups apply correspondingly to divalent alkyl groups, i.e. alkanediyl groups and alkylene groups, such as the methylene group —CH₂— and the polymethylene groups —CH₂—CH₂— and —CH₂—CH₂—CH₂— occurring in divalent alkylenedioxy groups such as —O—CH₂—O—, —O—CH₂—CH₂—O— or —O—CH₂—CH₂—CH₂—O—, and the groups C_(n)H_(2n), which can also be linear or branched and/or can be substituted by one or more, for example one, two, three, four or five, identical or different substituents which can be located in any desired positions. In general, the number of substituents can of course not exceed the number of hydrogen atoms in the unsubstituted parent system which can be replaced with a substituent and can be only one or two in the case of a CH₂ group, for example. Examples of the group C_(n)H_(2n), in which the number n is 1, 2, or 3, are —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—. If the number n in the group C_(n)H_(2n) is 0 (=zero), the two groups which are attached to the group C_(n)H_(2n) are directly connected to one another via a single bond. Similarly, if the group X is a direct bond, the groups R³ and Het are directly connected to one another via a single bond. The two free bonds of a divalent alkylenedioxy group can be connected to the same carbon atom or to different carbon atoms in the residual molecule, for example to two adjacent carbon atoms in an aromatic ring.

Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Substituted cycloalkyl groups can be substituted by one or more, for example one, two, three, four or five, identical or different substituents which can be located in any desired positions. In general, besides any other specified substituents, all cycloalkyl groups in the compounds of the formulae I and Ia, specifically cycloalkyl groups in the groups R¹ and R², can also carry one or more, for example one, two, three, four or five, identical or different (C₁-C₄)-alkyl substituents, for example methyl substituents, which can be located in any desired positions. Examples of alkyl-substituted cycloalkyl groups are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl.

If a group like phenyl, naphthalenyl and heteroaryl, including the group Het, which can be unsubstituted or substituted, is substituted by one or more substituents, in general it can carry one, two, three, four or five identical or different substituents, for example. The substituents can be located in any desired positions. Substituted heteroaryl groups can be substituted on ring carbon atoms and/or on suitable ring nitrogen atoms, i.e. on ring nitrogen atoms which in the parent ring system are capable of carrying a hydrogen atom or a substituent, where substituents on such substituted ring nitrogen atoms are in particular alkyl groups such as (C₁-C₄)-alkyl groups. Suitable ring nitrogen atoms, such as the ring nitrogen atoms in a pyridine ring or a quinoline ring, can also be present as N-oxides or as quaternary salts, the latter preferably having a counter-anion which is derived from a physiologically acceptable acid. In monosubstituted phenyl groups the substituent can be located in the 2-position, the 3-position or the 4-position. In a disubstituted phenyl group the substituents can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl groups the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. Naphthalenyl (=naphthyl) can be naphthalen-1-yl or naphthalen-2-yl. In monosubstituted naphthalen-1-yl groups the substituent can be located in the 2-, 3-, 4-, 5-, 6-, 7- or 8-position, in monosubstituted naphthalen-2-yl groups the substituent can be located in the 1-, 3-, 4-, 5-, 6-, 7- or 8-position. In disubstituted naphthalenyl groups the substituents can likewise occur in any desired positions in the ring via which the naphthalenyl group is bonded to the residual molecule, and/or in the other ring.

Unless stated otherwise in the respective definitions, heteroaromatic groups including heteroaryl groups and the group Het are preferably 5-membered or 6-membered monocyclic aromatic heterocyclic groups or 9-membered or 10-membered bicyclic aromatic heterocyclic groups, where the bicyclic groups contain a 6-membered ring fused to a 5-membered ring or two fused 6-membered rings. In bicyclic heteroaryl groups one or both rings can be aromatic, and one or both rings can contain heteroatom ring members. Preferably heteroaryl groups and other heterocyclic groups contain one, two or three, for example one or two, identical or different heteroatom ring members. The heteroatom ring members in heteroaryl groups and other heterocyclic groups are generally chosen from ring heteroatoms such as nitrogen, oxygen and sulfur, it being possible for suitable ring nitrogen atoms to carry a hydrogen atom or a substituent, such as the groups R⁴ and R¹⁰, as is the case in 5-membered aromatic heterocycles such as pyrrole, pyrazole, imidazole or triazole, or in bicyclic aromatic heterocycles such as benzoimidazole, for example. A monocyclic heteroaryl group or group Het which contains a group R⁴ or R¹⁰ can contain only one group R⁴ or R¹⁰, respectively, and is 5-membered. The heteroatom ring members in heteroaryl groups and other heterocyclic groups can be located in any desired positions provided that the resulting heterocyclic system is known in the art and is stable and suitable as a subgroup in a drug substance. For example, it is generally preferred that two atoms from the series O and S are not present in adjacent ring positions.

Examples of parent heterocycles of heteroaryl groups and other heterocyclic groups including the group Het are pyrrole, furan, thiophene, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole (=1,3-oxazole), isoxazole (=1,2-oxazole), thiazole (=1,3-thiazole), isothiazole (=1,2-thiazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, indole, benzothiophene, benzofuran, 1,3-benzodioxole (=1,2-methylenedioxybenzene), 1,3-benzoxazole, 1,3-benzothiazole, benzoimidazole, chroman, isochroman, 1,4-benzodioxane (=1,2-ethylenedioxybenzene), quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, thienothiophenes, 1,8-naphthyridine and other naphthyridines, acridine or pteridine. Heteroaryl groups, including heteroaryl groups representing R³, and other heterocyclic groups can be bonded via any desired suitable ring carbon atom and, in the case of nitrogen heterocycles, via any suitable ring nitrogen atom. Preferably they are bonded via a ring carbon atom. For example, thiophenyl (=thienyl) can be thiophen-2-yl or thiophen-3-yl, pyridinyl (=pyridyl) can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, imidazolyl can be, for example, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl or 1H-imidazol-5-yl, quinolinyl (=quinolyl) can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl or quinolin-8-yl. In monosubstituted pyridin-2-yl the substituent can be located in the 3-position, 4-position, 5-position or 6-position, in monosubstituted pyridin-3-yl the substituent can be located in the 2-position, 4-position, 5-position or 6-position, in monosubstituted pyridin-4-yl the substituent can be located in the 2-position or 3-position.

As far as applicable, the preceding explanations regarding heteroaryl groups apply correspondingly to groups which can be regarded as divalent heteroaryl groups, i.e. heteroarylene groups, such as the group Het in formulae I and Ia. In general, a divalent heteroaryl group can be bonded to the adjacent groups via any two desired suitable ring atoms including ring carbon atoms and/or, in the case of nitrogen heterocycles, ring nitrogen atoms. Preferably they are bonded via any two ring carbon atoms, in particular in the case of the group Het. In the case of a divalent bicyclic heteroaryl group, the positions via which it is bonded to the adjacent groups can be located in the same ring or in different rings. In the case of a divalent group derived from furan or thiophene, for example, the adjacent groups can be bonded in 2,3-position, 2,4-position, 2,5-position or 3,4-position. A divalent group derived from thiazole can be thiazole-2,4-diyl, thiazole-2,5-diyl or thiazole-4,5-diyl. A divalent group derived from pyridine can be pyridine-2,3-diyl, pyridine-2,4-diyl, pyridine-2,5-diyl, pyridine-2,6-diyl, pyridine-3,4-diyl or pyridine-3,5-diyl. In the case of an unsymmetrical divalent group the present invention includes all positional isomers, i.e., in the case of a pyridine-2,5-diyl group, for example, it includes the compound in which the one adjacent group is present in the 2-position and the other adjacent group is present in the 5-position as well as the compound in which the one adjacent group is present in the 5-position and the other adjacent group is present in the 2-position. Depending on the ranking order of the adjacent groups in the nomenclature of the compound, in the name of a compound the numbers of the locations of the adjacent groups may differ from the ones indicated above and, for example, a pyridine-2,5-diyl group may be designated as a pyridine-3,6-diyl group.

As far as applicable, the above explanations also apply correspondingly to the aromatic heterocycle which is formed by fusion of the group R³ to the group Het in case the group X is absent. In the respective compounds of the formula Ia the resulting polycyclic heteroaromatic group, which represents the R³—X-Het-moiety, is a bicyclic or tricyclic or tetracyclic ring system, preferably a bicyclic or tricyclic ring system, for example a bicyclic ring system, and contains one or more, for example one, two, three or four, identical or different heteroatom ring members chosen from those which can be present in the groups Het and R³. A phenyl or naphthalenyl or heteroaryl group representing R³ can be fused to, or condensed to, the group Het via any suitable bond in R³ and any suitable bond in the group Het, provided that the resulting polycyclic heteroaromatic group is known in the art and is stable and suitable as a subgroup in a drug substance and that in the resulting group at least the ring bonded to the group CR^(b) can be an aromatic ring, i.e. contain six conjugated pi electrons in case of a 5-membered or 6-membered monocyclic ring. For example, if the group Het in a compound of the formula Ia is a pyridine ring, X is absent and R³ is phenyl, the latter carbocyclic ring can be fused to the bond between positions 2 and 3 or the bond between positions 3 and 4 in the pyridine ring, and the resulting polycyclic heteroaromatic group representing the R³—X-Het-moiety is a quinolinyl or isoquinolinyl group. If a naphthalenyl group representing R³ is fused to a pyridine ring representing Het, the resulting polycyclic heteroaromatic group representing the R³—X-Het-moiety is an aza-anthracenyl or aza-phenanthrenyl group. The polycyclic heteroaromatic which is present in case X is absent, can be bonded to the group CR^(b) via any suitable ring atom, preferably a ring carbon atom, in an aromatic ring originating from the group Het, and can be substituted by substituents as outlined above for the groups R³ and Het.

The heterocyclic ring which can be formed by R¹ and R² together with the nitrogen atom which carries them, can be 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered, and can be saturated, i.e. contain no double bond within the ring, or unsaturated, including partially unsaturated and aromatic, in particular partially unsaturated, and contain, for example, one, two, three or four double bonds within the ring, provided the respective ring system is known in the art and is stable and suitable as a subgroup in a drug substance. Examples of residues of heterocyclic rings formed by R¹ and R² together with the nitrogen atom which carries them, are azetidin-1-yl, pyrrolidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperidin-1-yl, 1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl, azepan-1-yl, azocan-1-yl, azecan-1-yl, octahydrocyclopenta[b]pyrrol-1-yl, 2,3-dihydro-1H-indol-1-yl, octahydro-1H-indol-1-yl, 2,3-dihydro-1H-isoindol-2-yl, octahydro-1H-isoindol-2-yl, 1,2,3,4-tetrahydroquinolin-1-yl, decahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, decahydroisoquinolin-2-yl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl, pyrazolidin-1-yl, imidazolidin-1-yl, hexahydropyrimidin-1-yl, piperazin-1-yl, [1,3]diazepan-1-yl, [1,4]diazepan-1-yl, oxazolidin-3-yl, [1,3]oxazinan-3-yl, morpholin-4-yl, [1,3]oxazepan-3-yl, [1,4]oxazepan-4-yl, thiazolidin-3-yl, [1,3]thiazinan-3-yl, thiomorpholin-4-yl, [1,3]thiazepan-3-yl, [1,4]thiazepan-4-yl. As applies to the ring which can be formed by R¹ and R² together with the nitrogen atom carrying them in general, all listed examples of heterocyclic groups can be unsubstituted or substituted as indicated above, for example by R⁸. For example, they can be substituted on one or more, for example one, two or three, preferably one or two, more preferably one, ring carbon atoms by one or more, for example one, two, three or four, preferably one or two, identical or different substituents such as (C₁-C₄)-alkyl, for example methyl, and (C₁-C₄)-alkyloxycarbonyl, for example methoxycarbonyl, and/or on one or more ring nitrogen atoms by substituents such as (C₁-C₄)-alkyl, for example methyl, and (C₁-C₄)-alkyl-CO—, for example acetyl, which latter groups represent R⁹. Besides that, as applies to the ring which can be formed by R¹ and R² together with the nitrogen atom carrying them in general, ring sulfur atoms in the listed heterocyclic groups can carry one or two oxo groups, i.e. doubly bonded oxygen atoms, and thus become SO or SO₂ groups, i.e. sulfoxide or sulfone groups or S-oxides or S,S-dioxides. For example, the sulfur atom in a thiomorpholin-4-yl group can carry one or two oxo groups, and besides the thiomorpholin-4-yl group also the groups 1-oxo-thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl can be present in a compound of the invention.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

An oxo group, when bonded to a carbon atom, replaces two hydrogen atoms on a carbon atom of the parent system. Thus, if a CH₂ group is substituted by oxo, i.e. by a doubly bonded oxygen atom, it becomes a CO group. Evidently, an oxo group cannot occur as a substituent on a carbon atom in an aromatic ring.

The present invention includes all stereoisomeric forms of the compounds of the formulae I and Ia and their salts. With respect to each chiral center, independently of any other chiral center, the compounds of formulae I and Ia can be present in S configuration or substantially in S configuration, or in R configuration or substantially in R configuration, or as a mixture of the S isomer and the R isomer in any ratio. The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, compounds according to the invention which can exist as enantiomers can be present in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, and in the form of mixtures of the two enantiomers in all ratios including racemates. In the case of a E/Z isomerism, or cis/trans isomerism, for example on double bonds or rings, the invention includes both the E form and Z form, or the cis form and the trans form, as well as mixtures of these forms in all ratios. If desired, the preparation of individual stereoisomers can be carried out, for example, by separation of a mixture of isomers by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials in the synthesis, or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or Ia or at the stage of a starting material or an intermediate during the synthesis. The present invention also includes all tautomeric forms of the compounds of formulae I and Ia and their salts.

In case the compounds of the formulae I and Ia contain one or more acidic and/or basic groups, i.e. salt-forming groups, the invention also comprises their corresponding physiologically or toxicologically acceptable salts, i.e. non-toxic salts, in particular their pharmaceutically acceptable salts. Thus, the compounds of the formulae I and Ia which contain an acidic group can be present on such groups, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, quaternary ammonium salts such as tetraalkylammonium salts, or acid addition salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formulae I and Ia which contain a basic group, i.e. a group which can be protonated, can be present on such groups, and can be used according to the invention, for example, in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formulae I and Ia simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines or zwitterions. The salts of the compounds of the formulae I and Ia can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting the compound of the formula I or Ia with an organic or inorganic acid or base in a solvent or diluent, or by anion exchange or cation exchange from another salt. The present invention also includes all salts of the compounds of the formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts.

The present invention furthermore includes all solvates of compounds of the formulae I and Ia, for example hydrates or adducts with alcohols, active metabolites of the compounds of the formulae I and Ia, and also prodrugs and derivatives of the compounds of the formulae I and Ia which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds, for example esters or amides of carboxylic acid groups.

In the groups Y—CH₂ and Y—CH₂—CH₂ representing the group A the group Y is bonded to the group Het and the terminal CH₂ is bonded to the CO group depicted in formulae I and Ia. In the groups CH₂—Y and CH₂—CH₂—Y the group Y is bonded to the CO group depicted in formulae I and Ia, and the terminal CH₂ is bonded to the group Het. Preferably, the group A in the compounds of the formulae I and Ia is chosen from A is chosen from CH₂—CH₂, CH₂—CH₂—CH₂, Y—CH₂ and Y—CH₂—CH₂, more preferably from CH₂—CH₂, Y—CH₂ and Y—CH₂—CH₂, particularly preferably from CH₂—CH₂ and Y—CH₂. In one embodiment of the invention, A is chosen from the groups CH₂—CH₂ and CH₂—CH₂—CH₂ which do not contain a heteroatom Y, and preferably is CH₂—CH₂. In another embodiment of the invention, A is chosen from the groups Y—CH₂, CH₂—Y, Y—CH₂—CH₂ and CH₂—CH₂—Y which contain a heteroatom Y, and preferably is Y—CH₂ or Y—CH₂—CH₂, more preferably Y—CH₂. If CH₂ groups in the group A are substituted by substituents R⁴, the total number of substituents in the group A preferably is one, two, three or four, more preferably one, two or three, particularly preferably one or two. In one embodiment of the invention, the CH₂ groups in the group A are not substituted by substituents R⁴.

In the compounds of the formula Ia the divalent group Het is preferably defined as in the compounds of the formula I. More generally, one embodiment of the present invention relates to the use of a compound of the formula I, which is defined as above or below, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the stimulation of the expression of endothelial NO synthase and for the treatment of a disease in which such a stimulation, or an increase in NO level, is desired, for example a cardiovascular disorder such as atherosclerosis, coronary artery disease or cardiac insufficiency or any other diseases mentioned above or below herein.

More preferably, the divalent group Het in the compounds of the formulae I and Ia is a divalent aromatic group of the formula II

in which G is chosen from N and CH and L is chosen from S, O, NR⁴, CH═CH, CH═N and N═CH, and which can be substituted by one or more identical or different substituents R⁵, i.e. in which one or more ring carbon atoms can carry a substituent R⁵ instead of the hydrogen atoms which are implicitly present on the carbon atoms depicted in formula II or which are specified in the definition of the groups G and L, with the proviso that the ring system depicted in formula II comprises at least one heteroatom ring member, i.e. a group NR⁴ or an N, S or O atom, as a ring member. R⁵ and R⁴ in the ring system of the formula II are defined as indicated above with respect to the compounds of the formulae I and Ia. In one embodiment of the invention, G is N. In another embodiment of the invention, G is CH. In one embodiment of the invention, L is chosen from S, O, CH═CH, CH═N and N═CH. In another embodiment of the invention, L is chosen from S, NR⁴, CH═CH, CH═N and N═CH. In another embodiment of the invention, L is chosen from O, NR⁴, CH═CH, CH═N and N═CH. In another embodiment of the invention, L is chosen from S, CH═CH, CH═N and N═CH. In another embodiment of the invention, L is chosen from O, CH═CH, CH═N and N═CH. In another embodiment of the invention, L is chosen from NR⁴, CH═CH, CH═N and N═CH. In another embodiment of the invention, L is chosen from S, O and NR⁴. In another embodiment of the invention, L is S. In another embodiment of the invention, L is chosen from CH═CH, CH═N and N═CH. In a further embodiment of the invention, the group Het in the compounds of the formula I or Ia or the group of the formula II is chosen from the heteroarylene groups pyridinediyl, pyrimidinediyl, thiazolediyl, oxazolediyl, imidazolediyl, furandiyl and thiophenediyl, i.e. the divalent residues of pyridine, pyrimidine, thiazole, oxazole, imidazole, furan and thiophene, preferably from pyridinediyl, pyrimidinediyl, thiazolediyl, oxazolediyl, imidazolediyl and thiophenediyl, more preferably from pyridinediyl, thiazolediyl, oxazolediyl, imidazolediyl and thiophenediyl, particularly preferably from pyridinediyl, thiazolediyl and thiophenediyl, more particularly preferably from pyridinediyl and thiophenediyl, which can all be substituted by one or more identical or different substituents R⁵ and wherein one of the ring nitrogen atoms of the imidazolediyl group, which represents the nitrogen atom in the group NR⁴ in the definition of the group L, carries a group chosen from hydrogen and (C₁-C₄)-alkyl. In still a further embodiment of the invention the group Het in the compounds of the formula I or Ia or the group of the formula II is chosen from pyridinediyl, thiazolediyl, imidazolediyl and thiophenediyl, which can all be substituted by one or more identical or different substituents R⁵ and wherein one of the ring nitrogen atoms of the imidazolediyl group, which represents the nitrogen atom in the group NR⁴ in the definition of the group L, carries a group chosen from hydrogen and (C₁-C₄)-alkyl. In one embodiment of the invention the group Het in the compounds of the formula I or Ia or the group of the formula II is a 6-membered monocyclic aromatic group which contains one or two ring nitrogen atoms, i.e. one or two hetero ring members N, for example any of the groups pyridinediyl, pyridazinediyl, pyrimidinediyl and pyrazinediyl, and which can be substituted by one or more identical or different substituents R⁵. In another embodiment of the invention the group Het in the compounds of the formula I or Ia or the group of the formula II is a pyridinediyl group which can be substituted by one or more identical or different substituents R⁵. In another embodiment of the invention the group Het in the compounds of the formula I or Ia or the group of the formula II is a thiazolediyl group which can be substituted by one or more identical or different substituents R⁵. In another embodiment of the invention the group Het in the compounds of the formula I or Ia or the group of the formula II is a thiophenediyl group which can be substituted by one or more identical or different substituents R⁵. In one embodiment of the invention, the group Het in the compounds of the formula I or Ia or the group of the formula II cannot be a 5-membered monocyclic aromatic group which comprises at least one nitrogen ring member and one ring member chosen from oxygen and sulfur, such as a thiazolediyl or oxazolediyl group, which can all be substituted by one or more identical or different substituents R⁵, if simultaneously the group A is a group of the formula O—CH₂ wherein the oxygen atom is bonded to the group Het, for example to the thiazole or oxazole ring, and in which the CH₂ group can be substituted by (C₁-C₄)-alkyl, and/or Het cannot be an oxazolediyl group which is bonded to the group A via its 2-position and which carries an optionally substituted phenyl group representing the group R³—X in its 4-position and which can be substituted in its 5-position by a substituent R⁵, if simultaneously the group A is CH₂—CH₂ or CH₂—CH₂—CH₂, and/or Het cannot be an imidazolediyl group which is bonded to the group A via its 2-position and which can be substituted by a substituent R⁵, if simultaneously the group A is CH₂—Y or CH₂—CH₂—Y wherein Y is NR^(b) and all CH₂ groups can be substituted by one or more (C₁-C₄)-alkyl substituents and the terminal carbon atom is bonded to the group Het.

In one embodiment of the present invention the groups representing the group Het in the compounds of the formulae I and Ia or the group of the formula II, in which latter group the bonds via which it is connected to the groups R³—X and A are represented by the lines intersecting the ring sides, are bonded to the adjacent groups R³—X and A via any two ring carbon atoms or via any one ring carbon atom and a suitable ring nitrogen atom, where in the latter case preferably the nitrogen atom is bonded to the group R³—X and the carbon atom is bonded to the group A. In another embodiment of the invention the groups representing the group Het or the group of the formula II are bonded to the adjacent groups R³—X and A via any two ring carbon atoms. Preferably a pyridinediyl group representing Het or the group of the formula II is bonded to the adjacent groups via positions 3 and 6 of the pyridine ring, which positions may also be numbered as positions 5 and 2, respectively, depending on the ranking order of the groups bonded to the pyridine ring, or via positions 3 and 5, or via positions 2 and 6, particularly preferably via positions 3 and 6, where each of the groups R³—X and A can be present in each of the positions. I.e., in the latter pyridinediyl group, for example, which is bonded via positions 3 and 6, the group R³—X can be present in position 3 and the group A in position 6, as well as the group R³—X can be present in position 6 and the group A in position 3, where preferably the group R³—X is present in position 6 and the group A in position 3. A pyrimidinediyl group representing the group Het or the group of the formula II is preferably bonded to the adjacent groups via positions 2 and 5, where each of the groups R³—X and A can be present in each of the positions and preferably the group R³—X is present in position 2 and the group A is present in position 5. Preferably a group of the formula IIa,

which represents Het or the group of the formula II and in which L is O, S or NR⁴, i.e. which is an oxazolediyl, thiazolediyl or imidazolediyl group, is bonded to the adjacent groups via positions 2 and 5 or via positions 2 and 4, particularly preferably via positions 2 and 4, where each of the groups R³—X and A can be present in each of the positions and preferably the group R³—X is present in position 4 and the group A in position 2. Preferably a thiophenediyl or a furandiyl group which represents Het or the group of the formula II is bonded to the adjacent groups via positions 2 and 5 or via positions 2 and 4, which latter positions may also be numbered as positions 5 and 3, particularly preferably via positions 2 and 4, where each of the groups R³—X and A can be present in each of the positions and preferably the group R³—X is present in position 4 and the group A in position 2.

Preferred groups Het or groups of the formula II thus include the divalent heteroaromatic groups depicted in the following formulae IIIa to IIIg which represent preferred embodiments of the structural moiety R³—X-Het- in the compounds of the formulae I and Ia, and in which the heteroaromatic group can be unsubstituted or substituted by one or more identical or different substituents R⁵. In formulae IIIa to IIIg the line starting at a ring carbon atom represents the free bond by which the group is bonded to the group A.

Particularly preferred groups Het or groups of the formula II include the divalent heteroaromatic groups depicted in the formulae IIIb, IIIe and IIIg, especially the group depicted in formula IIIb, which represent particularly and especially preferred embodiments of the structural moiety R³—X-Het- in the compounds of the formulae I and Ia.

In the group CH₂—O representing the group X, the CH₂ group is bonded to the group R³ and the oxygen atom is bonded to the group Het. In the group O—CH₂, the group CH₂ is bonded to the group Het and the oxygen atom is bonded to the group R³. In one embodiment of the invention, the group X in the compounds of the formula Ia is defined as in the compounds of the formula I. Preferably, the group X in the compounds of the formulae I and Ia is chosen from a direct bond, CH₂ and O, in particular from a direct bond and O, or in the compounds of the formula Ia the group X is absent and in this case the phenyl, naphthalenyl or heteroaryl group representing the group R³ is fused to the group Het, provided that X cannot be O if the group R³—X— is bonded to a ring nitrogen atom of the group Het. In one embodiment of the present invention the group X in the compounds of the formulae I and Ia is chosen from a direct bond and O. In another embodiment of the present invention the group X in the compounds of the formulae I and Ia is a direct bond.

In a further embodiment of the present invention the group X in the compounds of the formula Ia is absent and in this embodiment the phenyl, naphthalenyl or heteroaryl group representing the group R³ is fused to the group Het. In still a further embodiment of the present invention the group X in the compounds of the formula Ia cannot be absent, i.e. in this embodiment the group X in the compounds of the formula Ia it is chosen from a direct bond, CH₂, O, CH₂—O, O—CH₂, S, NH and N((C₁-C₄)-alkyl) and preferably is defined as with respect to the compounds of the formula I.

In case the group X is absent, the phenyl, naphthalenyl or heteroaryl group representing the group R³ is fused to the group Het or the ring system depicted in formula II which contains the groups G and L. In case X is absent, in a particularly preferred embodiment of the present invention the structural moiety R³—X-Het- in the compounds of the formula Ia is a bicyclic heteroaryl group which comprises a monocyclic 5-membered or 6-membered heteroaromatic ring which represents the group Het and to which the group A is bonded, and a benzene ring which is fused to said heteroaromatic ring system and which represents the group R³, where the heteroaromatic ring can be substituted by one or more identical or different substituents R⁵ and the benzene ring can be substituted as indicated above with respect to R³. In case X is absent, the said structural moiety R³—X-Het- is more particularly preferably chosen from quinolinyl, isoquinolinyl, benzoimidazolyl, benzothiazolyl and benzothienyl, especially preferably from quinolinyl, benzoimidazolyl and benzothiazolyl, which are all bonded to the group A via the heterocyclic ring and which can be substituted as indicated.

Preferably, the group Y is chosen from O and NR^(b). In one embodiment of the invention, the group Y is O. In another embodiment of the invention, the group Y is S. In a further embodiment of the invention, the group Y is NR^(b).

The group R^(a) in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably, the group R^(a) in the compounds of the formulae I and Ia is chosen from methyl and fluorine. In one embodiment of the invention, the group R^(a) in the compounds of the formulae I and Ia is chosen from alkyl and oxo and preferably is (C₁-C₄)-alkyl, for example methyl. In another embodiment of the invention, the group R^(a) in the compounds of the formulae I and Ia is fluorine.

The group R^(b) in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably, the group R^(b) in the compounds of the formula I and Ia is chosen from hydrogen and methyl, and particularly preferably is hydrogen.

If the ring which can be formed by the groups R¹ and R² together with the nitrogen atom carrying them is a monocyclic ring system, in one embodiment of the invention it is saturated or partially unsaturated. More specifically, in one embodiment the ring is saturated or contains one or two double bonds within the ring, and in another embodiment it is saturated or contains one double bond within the ring, and in a further embodiment it is saturated. If the said ring is a bicyclic ring system, in one embodiment the specific ring of the bicyclic ring system to which the CO group depicted in formula Ia is bonded, is saturated or is partially unsaturated, and in a more specific embodiment this ring contains one or two double bonds within the ring of which one double bond can be common to both rings, and the second ring of the bicyclic ring system is a saturated or an aromatic ring, in particular an aromatic ring such as a benzene ring. In the compounds of the formula Ia a monocyclic ring formed by the groups R¹ and R² together with the nitrogen atom carrying them preferably contains 4, 5, 6 or 7 ring members, and a bicyclic ring system preferably contains 9 or 10 ring members. The ring which can be formed by the groups R¹ and R² together with the nitrogen atom carrying them is preferably a monocyclic ring system.

In one embodiment of the present invention, the ring which can be formed by the groups R¹ and R² together with the nitrogen atom carrying them can contain, in addition to the said nitrogen atom carrying R¹ and R², one further heteroatom ring member, i.e. one further ring heteroatom or heteroatom group, which is chosen from N, NR⁹, O, S, SO and SO₂ and preferably is chosen from NR⁹, O, S, SO and SO₂ and more preferably is chosen from NR⁹, O and S. If the heterocycle formed by R¹ and R² together with the nitrogen atom carrying them is substituted by one or more identical or different substituents R⁸, it preferably is substituted by one, two, three, four or five, more preferably by one, two, three or four, particularly preferably by one, two or three, more particularly preferably by one or two identical or different substituents R⁸ on ring carbon atoms, in addition to oxo groups on ring sulfur atoms and/or groups R⁹ on ring nitrogen atoms which may be present.

If R¹ and R², together with the nitrogen atom carrying them, form a ring, in one embodiment of the invention they form a saturated monocyclic 4-membered, 5-membered, 6-membered or 7-membered ring which, in addition to the nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member group chosen from NR⁹, O, S, SO and SO₂, preferably from NR⁹, O and S, wherein the ring can be substituted by one or more identical or different substituents R⁸. Examples of residues of such rings, from which the group —NR¹R² in the formulae I and Ia, which results if R¹ and R² together with the nitrogen atom carrying them form a ring, is preferably chosen, are azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, imidazolidin-1-yl, hexahydropyrimidin-1-yl, piperazin-1-yl, [1,3]diazepan-1-yl, [1,4]diazepan-1-yl, oxazolidin-3-yl, [1,3]oxazinan-3-yl, morpholin-4-yl, [1,3]oxazepan-3-yl, [1,4]oxazepan-4-yl, thiazolidin-3-yl, [1,3]thiazinan-3-yl, thiomorpholin-4-yl, [1,3]thiazepan-3-yl and [1,4]thiazepan-4-yl. Preferred such residues include azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, [1,4]oxazepan-4-yl, thiazolidin-3-yl and thiomorpholin-4-yl.

All rings formed by R¹ and R² together with the nitrogen atom carrying them can be substituted on carbon atoms by one or more identical or different substituents R⁸, and/or can carry on a ring nitrogen atom which is not bonded to the CO group, which is depicted in formulae I and Ia, a group R⁹ and/or can carry on a ring sulfur atom one or two oxo groups, to give a substituted group as indicated above. As examples of such substituted groups which are substituted by methyl, acetyl or methoxycarbonyl groups representing R⁸ and/or R⁹, and/or by an oxo group on a carbon atom representing R⁸, and/or by one or two oxo groups on a sulfur atom, and which can represent the group —NR¹R² in formulae I and Ia, the groups 2,6-dimethyl-piperidin-1-yl, 2,6-dimethyl-morpholin-4-yl, 4-methyl-piperazin-1-yl, 4-acetyl-piperazin-1-yl, 3-oxo-piperazin-1-yl, 4-methyl-3-oxo-piperazin-1-yl, 1-oxo-thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl may be mentioned.

If R¹ and R² do not form a ring together with the nitrogen atom carrying them, they preferably are independently of each other chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, more preferably from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, phenyl, phenyl-CH₂—, heteroaryl and heteroaryl-CH₂—, particularly preferably from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, phenyl and heteroaryl, and in each case R² can in addition be hydrogen, wherein the groups (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl can both be substituted by one or more identical or different substituents R⁶, and the groups phenyl and heteroaryl can both be substituted by one or more identical or different substituents R⁷. In one embodiment of the invention, in compounds in which R¹ and R² together with the nitrogen atom carrying them do not form a ring, R² is chosen from hydrogen and (C₁-C₄)-alkyl which can be substituted by one or more identical or different substituents R⁶, and R¹ is defined as indicated. In another embodiment of the invention, in compounds in which R¹ and R² together with the nitrogen atom carrying them do not form a ring, R² is hydrogen and R¹ is defined as indicated. In a further embodiment of the invention, in compounds in which R¹ and R² together with the nitrogen atom carrying them do not form a ring, R¹ and R² are defined as indicated, but none of them can be hydrogen. If R¹ and/or R² is an alkenyl group or an alkynyl group, preferably the nitrogen atom carrying R¹ and R² is not in conjugation with a double bond or triple bond, i.e., preferably the nitrogen atom carrying R¹ and R² is not directly bonded to a carbon atom in an alkenyl group or alkynyl group which is part of a double bond or triple bond.

In the compounds of the formula Ia the groups R¹ and R² are preferably defined as in the compounds of the formula I. More preferably, the groups R¹ and R² in the compounds of the formulae I and Ia are independently of each other chosen from (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and R² can in addition be hydrogen, wherein the groups (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₆)-alkenyl and (C₃-C₆)-alkynyl can all be substituted by one or more identical or different substituents R⁶, and the groups C_(n)H_(2n) can all be substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl, and all phenyl groups and heteroaryl groups can be substituted by one or more identical or different substituents R⁷,

or R¹ and R², together with the nitrogen atom which carries them, form a 4-membered to 7-membered monocyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring members chosen from N, NR⁹, O, S, SO and SO₂ which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R³.

Particularly preferably, the group R¹ in the compounds of the formulae I and Ia is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and the group R² is chosen from hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷, and wherein preferably the numbers n are independently of each other chosen from 0 and 1,

or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸.

More particularly preferably, the group R¹ in the compounds of the formulae I and Ia is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and the group R² is chosen from hydrogen and (C₁-C₄)-alkyl, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷, and wherein preferably the numbers n are independently of each other chosen from 0 and 1, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸.

Especially preferably, the group R¹ in the compounds of the formulae I and Ia is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl, phenyl and heteroaryl, and the group R² is chosen from hydrogen and (C₁-C₄)-alkyl, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷,

or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R³.

In one embodiment of the invention, the groups R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring member chosen from N, NR⁹, O, S, SO and SO₂, which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸, and preferably R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸, and more preferred features of this embodiment are those outlined above.

In the compounds of the formula Ia the group R³ is preferably chosen from phenyl, naphthalenyl and heteroaryl, more preferably from phenyl and heteroaryl, which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, ((C₁-C₄)-alkyl)-SO₂NH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, H₂NSO₂— and (C₁-C₄)-alkyl-SO₂—. Particularly preferably, the group R³ in the compounds of the formula Ia is defined as in formula I. More particularly preferably, the group R³ in the compounds of the formulae I and Ia is chosen from phenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—, and especially preferably by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, CF₃ and (C₁-C₄)-alkyl-SO₂—, and more especially preferably by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms and CF₃. A heteroaryl group representing R³ is preferably chosen from pyridinyl, thiophenyl and benzothiophenyl, more preferably from pyridinyl and thiophenyl. A heteroaryl group representing R³ is preferably bonded to the group X-Het via a ring carbon atom. In one embodiment of the invention the group R³ is phenyl which can be substituted as indicated. In another embodiment of the invention the group R³ is phenyl which is substituted as indicated. In another embodiment of the invention a phenyl group representing R³ is not phenyl which is substituted by an alkyl substituent in its 3-position, hydroxy in its 4-position and tert-butyl in its 5-position, if simultaneously the group X is a direct bond and the group Het is thiazolediyl which is bonded to the group A via its 2-position and which carries the phenyl group representing R³ in its 4-position. In a substituted group R³ the number of substituents preferably is one, two, three, four or five, more preferably one, two, three or four, particularly preferably one, two or three, more particularly preferably one or two. In one embodiment of the present invention the group R³ is a carbocyclic group, i.e. a phenyl group or a naphthalenyl group, and in another embodiment of the invention the group R³ is a monocyclic group, i.e. a phenyl group or a monocyclic heteroaryl group, where all these groups can be substituted as indicated.

Preferably, the group R⁴ in the compounds of the formulae I and Ia is chosen from hydrogen and methyl.

The group R⁵ in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably, the group R⁵ in the compounds of the formulae I and Ia is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—. Particularly preferably the group R⁵ in the compounds of the formulae I and Ia is chosen from halogen, (C₁-C₄)-alkyl, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CN and CF₃, more particularly preferably from halogen, (C₁-C₄)-alkyl, NH₂ and CF₃, especially preferably from halogen and (C₁-C₄)-alkyl, for example from fluorine, chlorine and methyl. In one embodiment of the invention the group Het in the compounds of the formulae I and Ia is unsubstituted or substituted by one or more identical or different substituents which are chosen from fluorine, chlorine, methyl, CF₃ and NH₂, and preferably are chosen from fluorine, chlorine. methyl and NH₂, and more preferably are chosen from fluorine, chlorine and methyl. In another embodiment of the invention the group Het in the compounds of the formulae I and Ia is unsubstituted. The number of substituents R⁵, which are present on a substituted group Het, preferably is one, two, three or four, more preferably one, two or three, particularly preferably one or two, more particularly preferably one.

The group R⁶ in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably the group R⁶ in the compounds of the formulae I and Ia is chosen from fluorine, (C₁-C₄)-alkyloxy, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl- and CF₃, more particularly preferably from fluorine and (C₁-C₄)-alkyloxy. The number of substituents R⁶ preferably is one, two or three, more preferably one or two, particularly preferably one.

The group R⁷ in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably the group R⁷ in the compounds of the formulae I and Ia is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy which can be substituted by one or more fluorine atoms, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃, SF₅ and (C₁-C₄)-alkyl-SO₂—, particularly preferably from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy which can be substituted by one or more fluorine atoms, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, CONH₂, CN, CF₃, SF₅ and (C₁-C₄)-alkyl-SO₂—, more particularly preferably from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy which can be substituted by one or more fluorine atoms, CN and CF₃, especially preferably from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, CN and CF₃, more especially preferably from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, and CF₃. The number of substituents R⁷ preferably is one, two, three or four, more preferably one, two or three, particularly preferably one or two, for example one.

The group R⁸ in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably the group R⁸ in the compounds of the formulae I and Ia is chosen from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, oxo, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂ and CF₃, particularly preferably from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, oxo, ((C₁-C₄)-alkyloxy)carbonyl- and CF₃, more particularly preferably from (C₁-C₄)-alkyl, oxo and ((C₁-C₄)-alkyloxy)carbonyl-, where an oxo substituent representing R⁸ can of course not be present in an aromatic ring in a ring system formed by R¹ and R² together with the nitrogen atom carrying them. The number of substituents R⁸ preferably is one, two, three, four or five, more preferably one, two, three or four, particularly preferably one, two or three, more particularly preferably one or two, for example one.

The group R⁹ in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably the group R⁹ in the compounds of the formulae I and Ia is chosen from hydrogen, (C₁-C₄)-alkyl and ((C₁-C₄)-alkyl)-CO—, particularly preferably from hydrogen and (C₁-C₄)-alkyl.

Preferably, the group R¹⁰ in the compounds of the formulae I and Ia is chosen from hydrogen and methyl.

In the compounds of the formula Ia a heteroaryl group is preferably defined as in the compounds of the formula I. Unless stated otherwise in the definition of any group containing a heteroaryl group, a heteroaryl group in the compounds of the formulae I and Ia is more preferably a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR¹⁰, O and S. Aromatic heterocyclic residues which can represent heteroaryl occurring in the groups R¹, R² and R³, for example, include pyridinyl, thiophenyl, thiazolyl and 1,3,4-oxadiazolyl.

The number n in the compounds of the formula Ia is preferably defined as in the compounds of the formula I. More preferably the number n in the compounds of the formulae I and Ia is 0 or 1, wherein all numbers n are independent of each other and can be identical or different. An example of the group phenyl-C_(n)H_(2n)— in which the number n is 1 is the benzyl group (=phenyl-CH₂—). If a group C_(n)H_(2n) is substituted by one or more substitutents, it is preferably substituted by one, two, three or four, more preferably by one, two or three, particularly preferably by one or two substituents, for example by one or two alkyl groups or by two fluorine atoms.

In preferred embodiments of the present invention one or more or all of the groups contained in the compounds of formulae I and Ia can independently of each other have any of the preferred definitions of the groups specified above or any one or some of the specific denotations which are comprised by the definitions of the groups and specified herein, all combinations of preferred definitions and/or specific denotations being a subject of the present invention. Also with respect to all preferred embodiments the invention includes the compounds of the formulae I and Ia in all their stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and their physiologically acceptable salts, as well as their tautomeric forms.

For example, one such embodiment relates to a compound and its use according to the present invention in which in formula I or formula Ia

A is chosen from CH₂—CH₂, Y—CH₂ and Y—CH₂—CH₂, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ or Y—CH₂—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond and O, provided that X cannot be 0 if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from methyl and fluorine; R^(b) is chosen from hydrogen and methyl; R¹ is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and R² is chosen from hydrogen, (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted on ring carbon atoms by one or more identical or different substituents R⁸; R³ is chosen from phenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁶ is chosen from fluorine, (C₁-C₄)-alkyloxy, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl- and CF₃; R⁷ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy which can be substituted by one or more fluorine atoms, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃, SF₅ and (C₁-C₄)-alkyl-SO₂—; R⁸ is chosen from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, oxo, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁹ is chosen from hydrogen, (C₁-C₄)-alkyl and ((C₁-C₄)-alkyl)-CO—; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered or 6-membered, monocyclic aromatic group which contains one, two or three identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; n is 0 or 1, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof.

Another such embodiment relates to a compound and its use according to the present invention in which in formula I or formula Ia

A is chosen from CH₂—CH₂ and Y—CH₂, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond and O, provided that X cannot be 0 if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from methyl and fluorine; R^(b) is chosen from hydrogen and methyl; R¹ is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and R² is chosen from hydrogen and (C₁-C₄)-alkyl, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted on ring carbon atoms by one or more identical or different substituents R⁸; R³ is phenyl which can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁶ is chosen from fluorine and (C₁-C₄)-alkyloxy; R⁷ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy which can be substituted by one or more fluorine atoms, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃, SF₅ and (C₁-C₄)-alkyl-SO₂—; R⁸ is chosen from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, oxo, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂ and CF₃; R⁹ is chosen from hydrogen, (C₁-C₄)-alkyl and ((C₁-C₄)-alkyl)-CO—; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; n is 0 or 1, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof.

Another such embodiment relates to the use of a compound according to the present invention in which in formula Ia

A is chosen from CH₂—CH₂ and Y—CH₂, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is absent and the phenyl group representing the group R³ is fused to the group Het, Y is chosen from O, S and NR^(b); R^(a) is chosen from methyl and fluorine; R^(b) is chosen from hydrogen and methyl; are independently of each other chosen from hydrogen and (C₁-C₄)-alkyl; R¹ is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and R² is chosen from hydrogen and (C₁-C₄)-alkyl, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted on ring carbon atoms by one or more identical or different substituents R⁸; R³ is phenyl which can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁶ is chosen from fluorine and (C₁-C₄)-alkyloxy; R⁷ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy which can be substituted by one or more fluorine atoms, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, CONH₂, CN, CF₃, SF₅ and (C₁-C₄)-alkyl-SO₂—; R⁸ is chosen from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, oxo, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₂)-alkylenedioxy, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂ and CF₃; R⁹ is chosen from hydrogen, (C₁-C₄)-alkyl and ((C₁-C₄)-alkyl)-CO—; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; n is 0 or 1, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof.

As in any embodiment of the invention, in the preceding embodiments, which contain exemplary definitions of compounds according to the invention, one or more or all of the groups can have any of its preferred definitions specified above or any one or some of the specific denotations which are comprised by their definitions and are specified above.

A further embodiment of the present invention relates to any of the individual compounds of the formulae I and Ia and their use according to the invention which are specifically disclosed herein, including the compounds of all examples described below, in the form of the respective free compound as well as in the form of the physiologically acceptable salts thereof in general and, if a specific salt is disclosed herein, in the form of this specific salt, as well as to all tautomeric forms of the free compounds and their salts if tautomeric forms exist. I.e., this embodiment encompasses the physiologically acceptable salts in general of any individual compound specifically disclosed herein, irrespective thereof whether the compound is specifically disclosed as the free compound or as a specific salt. For example, as regards the compound 2-[4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-N-(pyridin-2-yl)-acetamide, which is specifically disclosed as the free compound, subjects of the present invention are “2-[4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-N-(pyridin-2-yl)-acetamide” and “2-[4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-N-(pyridin-2-yl)-acetamide or a physiologically acceptable salt thereof”. As regards the compound 2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-1-(pyrrolidin-1-yl)-ethanone, for example, which is specifically disclosed as its trifluoroacetic acid salt, subjects of the present invention are “2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-1-(pyrrolidin-1-yl)-ethanone”, “2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-1-(pyrrolidin-1-yl)-ethanone or a physiologically acceptable salt thereof” and “2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-1-(pyrrolidin-1-yl)-ethanone trifluoroacetic acid salt”.

A further subject of the present invention are processes of preparation by which the compounds of the formulae I and Ia and salts thereof are obtainable and which are outlined in the following. There are several ways of preparing the compounds by assembling suitable building blocks. The synthetic strategies and the reaction types employed in these synthetic processes are per se known and are described in the literature, including the literature specifically referred to herein, and they can generally be performed under standard conditions which are familiar to one skilled in the art. In part, these processes comprise the reaction of a heteroaryl-substituted carboxylic acid or a derivative thereof of the formula IV with an amine of the formula V to give a compound of the formula I or Ia, where the compound of the formulae IV and/or the compound of the formula V can also be employed, and/or the compound of the formula I or Ia can also be obtained, in the form of a salt.

In the compounds of the formulae IV and V the groups A, Het, X, R¹, R² and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. As compounds of the formula IV, advantageously carboxylic acids or esters thereof such as an alkyl ester or benzyl ester can be employed, i.e. the group R in the compounds of the formula IV can be hydrogen or alkyl, for example (C₁-C₄)-alkyl like methyl or ethyl, or benzyl.

The reaction of a compound of the formula IV with a compound of the formula V to give a compound of the formula I or Ia can be performed under standard conditions for the conversion of a carboxylic acid or an ester thereof into a carboxamide or, from a different perspective, for the acylation of an amine by a carboxylic acid or an ester thereof. Compounds of the formula IV in which R is hydrogen, as well as compounds in which R is alkyl or benzyl, can be reacted with a compound of the formula V. If desired or more advantageous in a specific case, a compound of the formula IV in which COOR is a carboxylic acid group COOH can first be esterified and the obtained compound in which COOR is an ester group then reacted with a compound of the formula V. Likewise, a compound of the formula IV in which the group COOR is an ester group can first be cleaved to give the carboxylic acid, for example by acidic or basic saponification or by catalytic hydrogenation in the case of a benzyl ester, and the obtained compound in which COOR is a COOH group then reacted with a compound of the formula V. A compound of the formula IV in which COOR is an ester group, can be reacted with an amine of the formula V by combining the reactants at temperatures from about 20° C. to about 100° C. in a solvent, for example an ether like tetrahydrofuran (THF), dioxane, ethylene glycol dimethyl ether (1,2-dimethoxyethane, DME) or methyl tert-butyl ether (MTB), a hydrocarbon like dichloromethane, toluene or chlorobenzene, an alcohol like methanol, ethanol or isopropanol, an amide like dimethylformamide (DMF) or N-methylpyrrolidone (NMP), or another suitable solvent or a mixture of solvents. In the reaction of a compound of the formula IV in which the group COOR is a carboxylic acid group, preferably the latter group is first activated or converted into a reactive carboxylic acid derivative group. A suitable reactive carboxylic acid derivative is the carboxylic acid chloride, for example, which can be obtained by treatment of the acid with oxalyl chloride or thionyl chloride, for example. Suitable activating reagents for the carboxylic acid group include carbodiimides like N,N′-dicyclohexylcarbodiimide (DCC) or N,N′-diisopropylcarbodiimide (DIC), O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU), propanephosphonic acid anhydride (PPA), N,N′-carbonyldiimidazole (CDI), and chloroformic acid alkyl esters like ethyl chloroformate or isobutyl chloroformate which latter reagents lead to the formation of mixed anhydrides. The acylation of a compound of the formula V with a compound of the formula IV in which the group COOR is a carboxylic acid group, is generally carried out in a solvent such as, for example, toluene, dichloromethane, THF, dioxane, DME, DMF or NMP, in the presence of a base such as, for example, an amine like triethylamine, ethyldiisopropylamine or N-ethylmorpholine (NEM), or a basic alkali metal compound like sodium carbonate, sodium hydrogencarbonate, potassium carbonate or sodium acetate, or in the presence of an excess of the amine of the formula V, at temperatures from about 0° C. to about 80° C.

The intermediate compounds of the formula IV can be obtained by different processes. According to one of them, which relates to the preparation of a compound of the formula IVa, and thus the preparation of a final compound of the formula I or Ia, in which the group A is CH₂—CH₂, a compound of the formula VI,

i.e. a heteroarylacrylic acid derivative, is subjected to a hydrogenation, or reduction, of the double bond depicted in formula VI to give a single bond. In the compounds of the formula VI and IVa the groups Het, X and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH groups in the compound of the formula VI, which are part of the double bond depicted in the formula, and the CH₂ groups in the compound of the formula IVa depicted in the formula, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The group R in the compounds of the formulae VI and IVa is defined as in the compound of the formula IV.

The hydrogenation of the compound of the formula VI to give the compound of the formula IVa can be performed under standard conditions by means of molecular hydrogen in the presence of a hydrogenation catalyst or by means of a hydrogen donor compound such as a boron compound or a complex metal hydride, for example. Catalytic hydrogenations of the compounds of the formula VI with molecular hydrogen in the presence of a catalyst, which can be a heterogeneous or homogeneous catalyst, are generally carried out in the presence of a solvent, for example an alcohol like methanol or ethanol, an ether like THF, dioxane or DME, an acid like acetic acid, or a mixture of solvents, at temperatures from about 0° C. to about 50° C., for example at room temperature, at atmospheric pressure or elevated pressure, for example a pressure from about 1 atmosphere to about 10 atmospheres. As catalysts, advantageously transition metals, for example palladium, platinum, rhodium, ruthenium or nickel such as Raney nickel, or transition metal compounds, for example oxides such as platinum oxide or halides or phosphine complexes, are employed. A preferred catalyst is palladium on carbon, for example. As an example of a hydrogen donor compound, sodium borohydride may be mentioned which the presence of a metal halide such as bismuth trichloride in a solvent such as ethanol brings about the reduction of the carbon-carbon double bond in a compound of the formula VI.

Compounds of the formula VI can be obtained by condensing a compound of the formula VII, such as an aldehyde or a ketone, with a compound of the formula VIII in a reaction such as a Knoevenagel reaction, a Wittig reaction or a Wittig-Horner reaction, for example, to provide a heteroarylacrylic acid or derivative thereof of the formula VI.

In the compounds of the formulae VII and VIII the groups Het, X and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH group in the compound of the formula VII, which is part of the CHO group depicted in the formula, and the CH₂ group in the compound of the formula VIII depicted in the formula, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The group R in the compound of the formula VIII is defined as in the compound of the formula IV. Depending on the reaction performed, the group Q in the compound of the formula VIII can have different meanings. In case a Knoevenagel reaction is performed, the compound of the formula VIII can be malonic acid or a malonic acid derivative and the group Q can be a carboxylic acid group COOH or an ester group COOR in which R is (C₁-C₄)-alkyl or benzyl, for example. In such case the group COOR in the compound of the formula VIII can, independently of the group Q, also be a carboxylic acid group COOH or an ester group like COO—(C₁-C₄)-alkyl. In the Knoevenagel reaction also cyanoacetic acid and cyanoacetic acid derivatives such as (C₁-C₄)-alkyl esters can be employed, and the group Q can be a cyano group. Unless malonic acid or a monoester thereof is employed in the Knoevenagel reaction which generally react with decarboxylation and directly lead to the compound of the formula VI, the formation of a compound of the formula VI from compounds of the formulae VII and VIII in a Knoevenagel reaction may include the hydrolysis of an ester group or cyano group which may be performed in situ or in a separate step.

In case a Wittig reaction or a Wittig-Horner reaction is performed, in which case the group COOR in the compounds of the formula VIII is an ester group and R is (C₁-C₄)-alkyl or benzyl, for example, the compound of the formula VIII can be a phosphonium salt, for example a ((C₁-C₄)-alkyloxy)carbonylmethyltriphenylphosphonium halide which may carry an alkyl group representing R^(a) on the CH₂ group depicted in the formula, and the group Q then is a triphenylphosphonio group having a halide anion as counterion, or the compound of the formula VIII can be a phosphonate, for example a di((C₁-C₄)-alkyl)((C₁-C₄)-alkyloxy)carbonylmethylphosphonate which may carry an alkyl group representing R^(a) on the CH₂ group depicted in the formula, and the group Q then is a di((C₁-C₄)-alkyl)phosphonyl group. Instead of employing a ((C₁-C₄)-alkyloxy)carbonylmethyltriphenylphosphonium halide and deprotonating it when performing the reaction, also a stable phosphorus ylide, for example a ((C₁-C₄)-alkyloxy)carbonylmethylenetriphenylphosphane, can directly be employed in the reaction with the compound of the formula VIII.

The above-discussed reactions of compounds of the formulae VII and VIII to give compounds of the formula VI can generally be performed under standard conditions. For example, a Knoevenagel reaction with malonic acid or a malonic acid derivative can be performed by heating the reactants to temperatures from about 60° C. to about 120° C. in a solvent, for example a hydrocarbon like benzene, toluene or chlorobenzene, an alcohol like ethanol, or pyridine, preferably in the presence of a base such as an amine like piperidine, pyridine or β-alanine or an acid addition salt of an amine like ammonium acetate. Unless a stable phosphorus ylide is employed directly, a Wittig reaction or a Wittig-Horner reaction for providing a compound of the formula VI is generally performed under anhydrous conditions in a solvent, for example in an ether like THF, dioxane or DME or in an alcohol like ethanol, by first reacting the phosphonium salt or the phosphonate with a base, for example an alkali metal alcoholate like sodium methoxide or potassium tert-butoxide or an amide like lithium diisopropylamide or a hydride like sodium hydride or an organometallic compound like n-butyllithium, and then with a compound of the formula VII at temperatures from about −80° C. to about 100° C. Heteroarylacrylic acid derivatives of the formula VI can be obtained from aldehydes or ketones of the formula VII also by means of various other reactions which are well-known in the art. As an example, the Perkin reaction may be mentioned which can be applied for preparing compounds of the formula VI and in which the respective aldehyde of the formula VII is heated with an excess of a carboxylic acid anhydride, for example acetic anhydride, to temperatures from about 100° C. to about 150° C. in the presence of an alkali metal salt of the carboxylic acid, for example sodium acetate or potassium acetate.

In another process, heteroarylacrylic acids or derivatives thereof of the formula VI can be obtained from compounds of the formula IX and acrylic acid derivatives of the formula X in a Heck reaction.

In the compounds of the formulae IX and X the groups Het, X and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH group and the CH₂ group in the compound of the formula X, which groups are part of the double bond depicted in the formula, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The group COOR in the acrylic acid derivatives of the formula X preferably is an ester group and R is alkyl such (C₁-C₄)-alkyl, like methyl or ethyl, or benzyl, for example. The group L¹ in the compounds of the formula IX is a leaving group which is substitutable by an alkene moiety under the conditions of the Heck reaction, such as halogen, for example chlorine, bromine or iodine, or a sulfonyloxy group, for example trifluoromethanesulfonyloxy. Generally, the reaction is performed in the presence of a transition metal catalyst, such as a palladium catalyst, for example palladium acetate in the presence of a phosphane like triphenylphosphane or tri(ortho-tolyl)phosphane, or bis(triphenylphosphane)palladium chloride or tetrakis(triphenylphosphane)palladium, and a base, such as an amine, for example a tertiary amine like triethylamine, or a basic alkali metal salt, for example potassium carbonate or sodium acetate, in an inert solvent, such as a hydrocarbon, for example toluene, chlorobenzene or dichloromethane, an ether, for example DME, THF or dioxane, an amide, for example DMF or NMP, a nitrile, for example acetonitrile, or a mixture of solvents, at temperatures from about 20° C. to about 110° C.

The compounds of the formulae VII, VIII, IX and X as well as the compounds of the formula V and other starting compounds which are employed in the processes for the preparation of intermediates and the final compounds of the formulae I and Ia discussed herein, are commercially available or can be prepared according to standard procedures described in the literature or in analogy to such procedures. For example, aldehydes and ketones of the formula VII can be obtained by such procedures from the parent heteroarenes of the formula R³—X-Het-H or respective substituted heteroarenes which carry a substituent such as halogen, alkyl, carboxy, alkoxycarbonyl or cyano, for example, by means of a reaction such as a Friedel-Crafts acylation, a Vilsmeier formylation, a metalation followed by reaction with a carboxylic acid derivative, a halogenation of an alkyl group followed by hydrolysis, an oxidation of an alkyl group, or a reduction or a reaction with an organometallic compound of a cyano or carboxy group or a derivative thereof. Compounds of the formula IX can be obtained, for example, from the parent heteroarenes or respective substituted heteroarenes which carry a substituent such as hydroxy or amino by means of a reaction such as a halogenation of the parent heteroarene or a hydroxy-substituted heteroarene, a sulfonylation of a hydroxy group, or a diazotization of an amino group followed by reaction with halide.

The structural moiety R³—X may already be present in the compounds of the formulae VII and IX which are available or may be obtained as outlined afore, or it may be introduced by standard procedures in starting compounds of the compounds of the formulae VII and IX or their starting compounds. For example, compounds of the formulae VII and IX may be obtained from appropriate starting compounds of the formulae XI and XIV, or the formulae XV and XVI, respectively, by reaction with appropriate compounds of the formulae XII and XIII.

In the compounds of the formulae XI, XII, XIII, XIV, XV and XVI the groups Het and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. When performing the contemplated processes, also the C═O group in the compounds of formulae XI and XIV, which is depicted in the formulae, can be present in protected form or in the form of a precursor group. The CH group in the compounds of the formula XI and XIV, which is part of the CHO group depicted in the formulae, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The group X in the compounds of the formula XIV and XVI is chosen from 0, O—CH₂, S, NH and N((C₁-C₄)-alkyl). The group X in the compound of the XII is chosen from a direct bond, CH₂, O, O—CH₂, CH₂—O, S, NH and N((C₁-C₄)-alkyl). In case the group X in the compound of the XII and the obtained compound of the formula VII or IX is O, CH₂—O, S, NH or N((C₁-C₄)-alkyl), the group Z in the compound of the formula XII is hydrogen. In case the group X in the compound of the formula XII and the obtained compound of the formula VII or IX is a direct bond, the group Z can be a boronic acid group or a derivative thereof, for example a boronic acid group —B(OH)₂, and the compound of the formula XII thus can be a boronic acid of the formula R³—B(OH)₂. In case the group X in the compound of the formula XII is CH₂ or O—CH₂, the group Z can be a nucleophilically substitutable leaving group, for example halogen, in particular chlorine and bromine, or an arylsulfonyloxy or alkylsulfonyloxy group such as benzenesulfonyloxy, toluenesulfonyloxy, nitrobenzenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy, and the compound of the formula XII thus can be an alkylating agent. The group L¹ in the compounds of formulae XV and XVI is defined as in the compound of the formula IX or can be present in the form of a precursor group which is then converted into the desired group L¹, for example a hydroxy group or a protected hydroxyl group which can be converted into a trifluoromethanesulfonyloxy leaving group by treatment with trifluoromethanesulfonyl chloride. The group L² in the compounds of formulae XI and XV is a leaving group which can be replaced with the group R³—X— in a catalyzed or uncatalyzed nucleophilic aromatic substitution reaction or coupling reaction or a reaction of another type as it is performed when reacting the compounds of the formulae XI and XII or XV and XII. Examples of suitable leaving groups L² in the compounds of the formulae XI and XV are halogen, in particular chlorine, bromine and iodine, and sulfonyloxy groups such as trifluoromethanesulfonyloxy. The group L² in the compound of the formula XV can be identical to or different from the group L¹. If L¹ is a leaving group, the formation of the desired product of the formula IX in the reaction of the compounds of the formulae XV and XII can be achieved by applying suitable reaction conditions and employing a compound of the formula XV which contains two leaving groups L¹ and L² of different reactivity, or taking advantage of different reactivities of leaving groups which are present in different positions of the group Het in case L¹ and L² are identical. The latter situation applies to a compound of the formula XV such as 2,5-dibromopyridine, for example, in which the bromine atom in the 2-position is more reactive than the bromine atom in the 5-position. The group L³ in the compound of the formula XIII likewise is a nucleophilically substitutable leaving group and can be halogen, in particular chlorine, bromine and iodine, or a sulfonyloxy group like trifluoromethanesulfonyloxy, for example.

The reactions of the compounds of the formulae XI and XV with a compound of the formula XII and of the compounds of the formulae XIV and XVI with a compound of the formula XIII are generally performed in the presence of a base which binds the liberated acid of the formula L²-H or L³-H and/or enhances the nucleophilicity of compounds of the formulae XII, XIV and XVI which are alcohols, thiols or amines. Suitable bases include amines, for example tertiary amines like triethylamine, ethyldiisopropylamine, pyridine, amide salts, for example sodium amide or lithium diisopropylamide, organometallic compounds, for example organolithium compounds like n-butyllithium, alkali metal or alkaline earth metal hydrides, for example lithium hydride, sodium hydride or calcium hydride, alkali metal or alkaline earth metal hydroxides or quaternary ammonium hydroxides, for example lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, benzyltrimethyl-ammonium hydroxide, alkali metal or alkaline earth metal alkoxides, for example sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, or other basic alkaline metal or alkaline earth metal compounds, for example carbonates like sodium carbonate, potassium carbonate, cesium carbonate, hydrogencarbonates like sodium hydrogencarbonate, potassium hydrogencarbonate, or other basic salts, or a mixture of bases. By means of the base, the compounds of the formula XII, XIV and XVI, which are alcohols, thiols or amines, can initially be converted into their corresponding salts. The reactions, which are nucleophilic arylation reactions and which can be performed in the presence or absence of a catalyst such as transition metal compound, are usually carried out in an inert solvent, such as a hydrocarbon or chlorinated hydrocarbon, for example n-heptane, toluene, xylene, chlorobenzene, dichloromethane, an ether, for example diethyl ether, diisopropyl ether, DME, THF, dioxane, an ester, for example ethyl acetate or butyl acetate, an amide, for example DMF or NMP, a nitrile, for example acetonitrile, an alcohol, for example methanol, ethanol, isopropanol, n-butanol, or another solvent, for example pyridine or dimethyl sulfoxide (DMSO), or a mixture of solvents. The reactions are generally performed at temperatures from about −20° C. to about 130° C.

In case the group X is a direct bond and the group Z in the compound of the formula XII is a boronic acid group —B(OH)₂ or a derivative thereof, the reaction of the compound of the formula XII with a compound of the formula XI or XV to give a compound of the formula VII or IX, in which X is a direct bond, can be carried out under the conditions of the well known Suzuki coupling, or Suzuki-Miyaura coupling, in the presence of a transition metal catalyst in an aqueous or non-aqueous solvent, for example a mixture of an ether such as DME and water. Suitable catalysts include palladium catalysts, for example tetrakis(triphenylphosphane)palladium or palladium acetate. Details on such coupling reactions of boronic acid derivatives, which can advantageously be used also in other processes for the preparation of the compounds of the invention, and intermediates therefor are explained in Kotha et al., Tetrahedron 58 (2002) 9633; Miyaura, Topics in Current Chemistry 219 (2002) 11; or Walker et al., Angew. Chem. Ind. Ed. 43 (2004) 1871, for example. If the group X is CH₂ or O—CH₂ and the compound of the formula XII is an alkylating agent as specified above, the reaction of a compound of the formula XII with a compound of the formula XI or XV to give a compound of the formula VII or IX, in which X is CH₂ or O—CH₂, can be carried out by metalating the compound of the formulae XI or XV, for example by means of an organolithium compound such as n-butyllithium, and then alkylating it with the compound of the formula XII or reacting it with an aldehyde of the formula R³—CHO to give a compound containing the group R³—CH(OH)— which is then reduced to the group R³—CH₂—. An R³—CH₂— group representing the group R³—X— can also be introduced into a compound of the invention by performing an acylation reaction with a suitable starting compound to give a compound which contains the group R³—CO— and reducing this group to the group R³—CH₂—. As is usual and applies to all reactions performed in the synthesis of a compound of the invention, the detailed conditions of a specific preparation, including the solvent, the base, the temperature, the order of addition, the molar ratios and other parameters, are routinely chosen by the skilled person in view of the characteristics of the starting compounds and the target compound.

The order in which the structural moieties in a compound of the invention are introduced to give the final compound of the formula I or Ia, or in which transformations of groups are performed, is variable and can be adapted to the needs and desire in a specific case. For example, instead of first hydrogenating a compound of the formula VI to give a compound of the formula IVa, and then reacting the compound of the formula IVa with an amine of the formula V, it is also possible first to react the compound of the formula VI with an amine of the formula V to give a compound of the formula XVII, and then hydrogenate the compound of the formula XVII to give a compound of the formula Ib, i.e. a compound of the formula I or Ia in which A is CH₂—CH₂.

In the final compound of the formula Ib the groups Het, X, R¹, R² and R³ are defined as in the compounds of the formulae I and Ia. The CH₂ groups in the compounds of the formula Ib, which are depicted in the formula, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. In the compounds of the formula XVII the groups Het, X, R¹, R² and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH groups in the compound of the formula XVII, which are part of the double bond depicted in the formula, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The explanations given above on the reaction of the compound of the formula IV with the compound of the formula V to give the compound of the formula I or Ia, and the hydrogenation of the compound of the formula VI to give the compound of the formula IVa, apply correspondingly to the reaction of the compound of the formula VI with the compound of the formula V to give the compound of the formula XVII, and the hydrogenation of the compound of the formula XVII to give the compound of the formula Ib, respectively.

In a further synthetic approach, besides by performing the processes for the preparation of the intermediates of the formula VI outlined above in which the group R³—X— is present in the starting compounds of the formulae VII and IX which are reacted with the compounds of the formulae VIII and X, respectively, just so the starting compounds of the formulae XI and VIII, or the starting compounds of the formulae XV and X, may be reacted to give the intermediate of the formula XVIII which does not yet contain the group R³—X— and in which this group is introduced by reaction with a compound of the formula XII to give a compound of the formula VI.

In the compound of the formula XVIII the group Het is defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH groups in the compound of the formula XVIII, which are part of the double bond depicted in the formula, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The group R in the compound of the formula XVIII is defined as in the compound of the formula IV and can thus be hydrogen, (C₁-C₄)-alkyl or benzyl, for example. The group L² in the compound of the formula XVIII is defined as in the compounds of the formulae XI and XV. The explanations given above on the reaction of the compound of the formula VII with the compound of the formula VIII, the reaction of the compound of the formula IX with the compound of the formula X, and the reaction of the compounds of the formulae XI and XV with the compound of the formula XII apply correspondingly to the reaction of the compound of the formula XI with the compound of the formula VIII, the reaction of the compound of the formula XV with the compound of the formula X, and the reaction of the compound of the formula XVIII with the compound of the formula XII, respectively. Similarly as explained above, the formation of a compound of the formula XVIII in which R is hydrogen may thus include the cleavage of an ester group to provide a carboxylic acid group. Analogously, in a further approach for the synthesis of a compound of the formula VI, the starting compounds of the formulae XIV and VIII, or the starting compounds of the formulae XVI and X, may be reacted to give an intermediate which differs from the compound of the formula XVIII in that it contains the group HX— instead of the group L², wherein X is chosen from O, O—CH₂, S, NH and N((C₁-C₄)-alkyl) and into which the group R³ is then introduced by reaction with a compound of the formula XIII to give a compound of the formula VI.

The moiety —NR¹R² can also be introduced prior to the moiety R³—X and, for example, an intermediate compound of the formula XVIII reacted with an amine of the formula V to give a compound of the formula XIX which is then reacted with a compound of the formula XII to give an intermediate compound of the formula XVII which is subsequently hydrogenated to give a compound of the formula Ib as outlined above.

In the compound of the formula XIX the groups Het, R¹ and R² are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH groups in the compound of the formula XIX, which are part of the double bond depicted in the formula, can optionally be substituted by a suitable substituent representing R^(a), for example an alkyl substituent. The explanations given above on the reaction of the compound of the formula IV with the compound of the formula V, and on the reaction of the compounds of the formulae XI and XV with the compound of the formula XII, apply correspondingly to the reaction of the compound of the formula XVIII with the compound of the formula V, and the reaction of the compound of the formula XIX with the compound of the formula XII, respectively. Thus, for example, a compound of the formula XVIII in which the group COOR is an ester group, as well as a compound in which the group COOR is a carboxylic acid group COOH, can be reacted with a compound of the formula V, where in the latter case the carboxylic acid group is preferably activated or converted into a reactive carboxylic acid derivative group, for example into the carboxylic acid chloride. As explained above, in case the group X is a direct bond, the group R³—X is preferably introduced by means of a compound of the formula XII in which Z is a boronic acid group or a derivative thereof, for example a boronic acid of the formula R³—B(OH)₂, under the conditions of the Suzuki reaction.

Intermediate compounds of the formula IV in which the group A is CH₂—CH₂—CH₂, i.e. compounds of the formula IVb, which can be reacted with compounds of the formula V to give final compounds of the formula Ic as outlined above with respect to the reaction of the compounds of the formulae IV and V, can be obtained by different processes, for example by chain elongation of the intermediates of the formula IVa which can in turn be obtained as outlined afore.

In the final compound of the formula Ic the groups Het, X, R¹, R² and R³ are defined as in the compounds of the formulae I and Ia. The CH₂ groups in the compounds of the formula Ic, which are depicted in the formula, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. In the compounds of the formulae XX, XXI and IVb the groups Het, X and R³ are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH₂ groups in the compounds of the formulae XX, XXI and IVb, which are depicted in the formulae, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. The group R in the compound of the formula IVb is defined as in the compound of the formula IV. The group L⁴ in the compound of the formula XXI is halogen, in particular chlorine, bromine or iodine, or another group which is substitutable in a nucleophilic aliphatic substitution reaction, for example an arylsulfonyloxy or alkylsulfonyloxy group such as benzenesulfonyloxy, toluenesulfonyloxy, nitrobenzenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy.

According to one procedure for the chain elongation of a compound of the formula IVa, a compound of the formula IVa in which R is hydrogen, i.e. a carboxylic acid which may in turn be obtained by ester cleavage from a compound of the formula IVa in which R is (C₁-C₄)-alkyl or benzyl, for example by hydrolysis in the presence of an acid or a base, is first converted into the carboxylic acid chloride by treatment with oxalyl chloride or thionyl chloride, and the acid chloride is then reacted with diazomethane under the conditions of the Arndt-Eistert reaction, for example in a solvent such as an ether like diethyl ether in the presence of a silver catalyst like silver benzoate, to give a compound of the formula IVb in which R is hydrogen or (C₁-C₄)-alkyl upon workup with water or an alkanol, respectively. In another procedure, a compound of the formula IVa is first reduced under standard conditions to the alcohol of the formula XX, for example by treatment with a complex hydride reducing agent such as lithium aluminium hydride or lithium borohydride, for example, in a solvent such as an ether like diethyl ether, THF, DME or diethylene glycol dimethyl ether. The hydroxy group in the compound of the formula XX is converted into a nucleophilically substitutable leaving group L⁴, for example by treatment with a hydrohalic acid like hydrogen bromide or hydrogen iodide or with thionyl chloride or phosphorus tribromide, or by treatment with an arylsulfonyl chloride or alkylsulfonyl chloride or anhydride like tosyl chloride or methanesulfonyl chloride, to give a compound of the formula XXI. The compound of the formula XXI is then reacted with a cyanide, for example with sodium cyanide in an aprotic solvent such as DMSO or an amide like DMF or with trimethylsilyl cyanide, to give a nitrile which can easily be hydrolyzed to the compound of the formula IVb in which R is hydrogen. In a further procedure, a Grignard reaction is performed in which the compound of the formula XXI, in which L⁴ is chlorine, bromine or iodine, is first reacted with magnesium and then with carbon dioxide or an alkyl chloroformate such as ethyl chlorofomate to give a compound of the formula IVb.

Intermediate compounds of the formula IV in which A is Y—CH₂ or Y—CH₂—CH₂, i.e. compounds of the formula IVc, which can be reacted with compounds of the formula V to give final compounds of the formula Id as outlined above with respect to the reaction of the compounds of the formulae IV and V, can be obtained by reaction of a compound of the formula IX with a compound of the formula XXII or by reaction of a compound of the formula XXIII with a compound of the formula XXIV, for example.

In the final compound of the formula Id the groups Het, X, R¹, R² and R³ are defined as in the compounds of the formulae I and Ia. The number t in the compounds of the formulae Id, IVc, XXII and XXIV is 1 or 2. The CH₂ groups in the compounds of the formulae Id, IVc, XXII and XXIV, which are depicted in the formulae, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. The group Y in the compounds of the formulae Id, IVc, XXII and XXIII is defined as in the compounds of the formulae I and Ia. The groups Het, X and R³ in the compounds of the formulae IVc and XXIII are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The group R in the compounds of the formulae IVc, XXII and XXIV is defined as in the compound of the formula IV. Preferably, the group COOR in the compounds of the formulae XXII and XXIV and in the initially obtained compounds of the formula IVc is an ester group or another protected form of a carboxylic acid group, and R is alkyl such as (C₁-C₄)-alkyl, like methyl, ethyl or tert-butyl, or benzyl, for example. The formation of a compound of the formula IVc in which R is hydrogen may thus include the cleavage of an ester group to provide a carboxylic acid group. The group L⁵ in the compound of the formula XXIV is defined as the group L⁴ in the compound of the formula XXI and is halogen or another group which is substitutable in a nucleophilic aliphatic substitution reaction, for example bromine.

The explanations given above on the reaction of the compound of the formula XII in which X is O, CH₂—O, S, NH or N((C₁-C₄)-alkyl) and Z is hydrogen, with a compound of the formula XI or a compound of the formula XV, apply analogously to the reaction of the compound of the formula XXII with the compound of the formula IX and the reaction of the compound of the formula XXIII with the compound of the formula XXIV. Thus, the latter reactions are generally performed in a solvent in the presence of a base which binds the liberated acid of the formula L¹-H or L⁵-H and/or enhances the nucleophilicity of the compounds of the formula XXII and XXIII which contain an OH, SH or NH group which group is arylated or alkylated by the compound of the formula IX or XXIV, respectively. Example of bases which may be used in the latter reactions, are amines, for example tertiary amines like triethylamine or ethyldiisopropylamine, alkali metal hydrides like sodium hydride, alkali metal hydroxides like sodium hydroxide or potassium hydroxide, alkali metal alkoxides like sodium methoxide, sodium ethoxide or potassium tert-butoxide, or other basic alkaline metal compounds such as carbonates like sodium carbonate, potassium carbonate or cesium carbonate. By means of the base, the compounds of the formulae XXII and XXIII can initially be converted into their corresponding salts. The reactions can be performed in the presence or absence of a catalyst such as a transition metal compound. Examples of solvents which may be used, are ethers like DME, THF or dioxane, amides like DMF or NMP, or DMSO. The reactions are generally performed at temperatures from about 0° C. to about 130° C. A compound of the formula IVc in which the number t is 2, may also be obtained from a compound of the formula XXIII and a compound of the formula X in an addition reaction of the YH moiety in the compound of the formula XXIII to the double bond in the compound of the formula X in the presence of a base.

Like in the preparation of compounds in which A is CH₂—CH₂ or CH₂—CH₂—CH₂, the order in which the structural moieties are introduced can be varied also in the preparation of other compounds of the formulae I and Ia including compounds of the formula Id in which A is Y—CH₂ or Y—CH₂—CH₂. For example, besides with compounds of the formulae IX and XXIII which already contain the moiety R³—X, the compounds of the formulae XXII and XXIV can also be reacted with the compounds of the formulae XV and XXV, respectively, to give the intermediate compound of the formula XXVI which can be converted into a final compound of the formula Id via an intermediate of the formula XXVII or an intermediate of the formula IVc.

The groups Het, R¹ and R² in the compounds of the formulae XXV, XXVI and XXVII are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The CH₂ groups in the compounds of the formulae XXVI and XXVII, which are depicted in the formulae, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. The number t in the compounds of the formulae XXVI and XXVII is 1 or 2. The group Y in the compounds of the formulae XXV, XXVI and XXVII is defined as in the compounds of the formulae I and Ia. The group R in the compound of the formulae XXVI is defined as in the compound of the formula IV. The group L² in the compounds of the formulae XXV and XXVI is defined as in the compounds of the formulae XI and XV. The explanations given above on other procedures for the preparation of compounds of the formula I or Ia apply correspondingly to the reactions which are performed in the preparation of the compounds of the formula Id from the compounds of the formulae XV and XXII or the compounds of the formulae XXV and XXIV via the intermediates of the formulae XXVI, XXVII and IVc.

Intermediate compounds of the formula IV in which A is CH₂—Y or CH₂—CH₂—Y, i.e. compounds of the formula IVd′ or the formula IVd″, which can be reacted with compounds of the formula V to give final compounds of the formula Ie as outlined above with respect to the reaction of the compounds of the formulae IV and V, can be obtained by reaction of a compound of the formula XXVIII with a chloroformate of the formula XXIX or with phosgene of the formula XXX or a phosgene equivalent like diphosgene. Compounds of the formula Ie can advantageously also be prepared by reaction of a compound of the formula XXVIII with a carbamyl chloride of the formula XXXI in case R¹ and R² are different from hydrogen, or with an isocyanate of the formula R¹—N═C═O in case R² in the compound of the formula Ie is hydrogen.

In the final compound of the formula Ie the groups Het, X, R¹, R² and R³ are defined as in the compounds of the formulae I and Ia. The number t in the compounds of the formulae Ie, IVd′, IVd″ and XXVIII is 1 or 2. The CH₂ groups in the compounds of the formulae Ie, IVd′, IVd″ and XXVIII, which are depicted in the formulae, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. The group Y in the compounds of the formulae Ie, IVd′, IVd″ and XXVIII is defined as in the compounds of the formulae I and Ia. The groups Het, X, R¹, R² and R³ in the compounds of the formulae Ie, IVd′, IVd″ and XXVIII are defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The group R in the compounds of the formulae IVd′ and XXIX is alkyl such (C₁-C₄)-alkyl, like methyl or ethyl, for example. The compounds of the formula IVd″ can be regarded as reactive carboxylic acid derivative of the compounds of the formula IVd′ in which R is hydrogen which latter compounds are not stable. The group R in the compounds of the formulae XXIX and IVd′ can also have other meanings such as phenyl or substituted phenyl like 4-nitrophenyl which allow the substitution of the group OR with the group NR¹R² in the reaction of the compounds of the formulae IVd′ and V.

The reaction of the compound of the formula XXVIII with the compounds of the formulae XXIX, XXX and XXXI, as well as the reaction of the compounds of the formulae IVd′ and IVd″, which compounds may be prepared in situ and reacted further without isolation, with the compound of the formula V is generally performed in an aprotic solvent, for example a hydrocarbon like toluene, xylene, chlorobenzene or dichloromethane, an ether like THF, dioxane, DME or diethylene glycol dimethyl ether, or an ester like ethyl acetate or butyl acetate, in the presence of a base, for example a tertiary amine like triethylamine, ethyldiisopropylamine, NEM or pyridine. The compounds of the formula XXVIII can be obtained from compounds of the formula VII, for example. Compounds of the formula XXVIII in which Y is O and t is 1 can be prepared from the compound of the formula VII by reduction of the CO group depicted in the formula to an alcohol, for example by means of complex hydride reducing agent such as lithium aluminum hydride, lithium borohydride or sodium borohydride. For the preparation of compounds of the formula XXVIII in which Y is S or NR^(b), the hydroxy group in the said alcohol can be converted into a leaving group such as halogen or arylsulfonyloxy or alkylsulfonyloxy as outlined above with respect to the conversion of the compound of the formula XX into the compound of the formula XXI, and the obtained alkylating compound reacted with an amine of the formula R^(b)NH₂ or hydrogen sulfide or a salt or an equivalent thereof. Compounds of the formula XXVIII in which t is 2 can be obtained, for example, by elongating the carbon chain in the compound of the formula VII by one carbon atom, for example by performing a Wittig reaction of the compound of the formula VII with a methoxymethyltriphenylphosphonium salt and a base, hydrolyzing in the intermediate compound of the formula R³—X-Het-CH═CH—OCH₃ the vinyl ether moiety under acidic conditions to give the aldehyde of the formula R³—X-Het-CH₂—CHO, and reducing the latter to give the alcohol of the formula R³—X-Het-CH₂—CH₂—OH as explained afore. Compounds of the formula XXXI can be obtained from the compound of the formula V with phosgene of the formula XXX or an equivalent thereof.

Further synthetic strategies for the preparation of compounds of the invention include the assembly of the group Het in a ring-forming reaction from starting compounds which may contain the groups R³—X— or part of this group or a protected form or precursor thereof which is then modified in subsequent reaction steps. For example, compounds of the formulae I and Ia in which the group Het is a thiazole ring, the group X is a direct bond and the group A is CH₂—CH₂, can be prepared by reacting a 2-bromo-1-R³-ethanone of the formula XXXII, in which the CH₂ group can optionally be substituted by a suitable substituent representing R⁵, for example an alkyl substituent, with a 2-oxo-thiocarboxamide in which the oxo group is protected, for example as a ketal or acetal, for example with a 2,2-diethoxythioacetamide derivative of the formula XXXIII, to give a compound of the formula XXXIV. Subsequent deprotection of the oxo group yields a compound of the formula VIIIa which is then reacted with a compound of the formula VIII to give an intermediate of the formula VIa. Hydrogenation of the compound of the formula VIa to give the intermediate of the formula IVe and subsequent reaction with an amine of the formula V finally provides a compound of the formula I or Ia.

In the compounds of the formulae XXXII, XXXIII, XXXIV, VIIa, Via and IVe the group R³ is defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. Like the CH₂ group in the compound of the formula XXXII, the thiazole ring in the compounds of the formulae XXXIV, VIIa, Via and IVe can be substituted by a suitable substituent such as an alkyl group. The CH groups in the compounds of the formulae XXXIII, XXXIV, VIIa and Via and the CH₂ groups in the compound of the formula IVe, which are depicted in the formulae, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. The group R in the compound of the formula VIa and IVe is defined as in the compound of the formula IV and can thus be hydrogen, (C₁-C₄)-alkyl or benzyl, for example, where the formation of a compound of the formula VIa or IVe in which R is hydrogen may include the cleavage of an initially formed ester. The groups R^(p) in the compounds of the formulae XXXIII and XXXIV can be alkyl groups, such as methyl or ethyl, or together be an alkanediyl group, such as an 1,2-ethanediyl group. The reaction of the compounds of the formulae XXXII and XXXIII is generally carried out in a solvent, for example an alcohol like as methanol or ethanol, an ester like ethyl acetate or butyl acetate, or an ether like THF, dioxane or DME, at temperatures from about 20° C. to about 80° C. The cleavage of the acetal or ketal group in the compound of the formula XXXIV to give the free oxo group can be performed by treatment with a dilute acid, for example hydrochloric acid or sulfuric acid, at temperatures from about 20° C. to about 60° C., and the subsequent reaction with the compound of the formula VIII and the hydrogenation can be performed under the conditions outlined above with respect to the reaction of the compounds of the formulae VII and VIII and with respect to the hydrogenation of the compounds of the formula VI.

Another example of a procedure for the preparation of compounds of the invention in which the group Het is assembled in a ring forming reaction, is the preparation of compounds in which the group Het is a thiazole ring, the group X is a direct bond and the group A is NR^(b)—CH₂, which can be prepared by reacting a 2-bromo-1-R³-ethanone of the formula XXXII, in which the CH₂ group can optionally be substituted by a suitable substituent representing R⁵, for example an alkyl substituent, with sodium thiocyanate of the formula XXXV and an aminoacetic acid ester of the formula XXIIa to give an intermediate of the formula IVf which upon reaction with an amine of the formula V provides a compound of the formula I or Ia.

In the compound of the formula IVf the group R³ is defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. Like the CH₂ group in the compound of the formula XXXII, the thiazole ring in the compound of the formula IVf can be substituted by a suitable substituent such as an alkyl group. The CH₂ groups in the compounds of the formulae XXIIa and IVe, which are depicted in the formulae, can optionally be substituted by suitable substituents representing R^(a), for example alkyl substituents. The group R in the compounds of the formula XXIIa and IVf is defined as in the compound of the formula IV and can thus be hydrogen, (C₁-C₄)-alkyl or benzyl, for example, where the formation of a compound of the formula IVf in which R is hydrogen may include the cleavage of an initially formed ester. The reaction of the compounds of the formulae XXXII, XXXV and XXIIa is preferably carried out in an alcohol like methanol or ethanol at temperatures from about 20° C. to about 80° C.

As a further example of a process for the preparation of compounds of the invention which includes the assembly of the group Het in a ring-forming reaction, the preparation of compounds in which the group Het is a pyrimidine ring, the group X is a direct bond and the group A is CH₂—CH₂, may be mentioned. Such compounds can be obtained by reacting an amidine of the formula XXXVI with a suitable triformylmethane derivative, for example a 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane salt like the bis(tetrafluoroborate) of the formula XXXVII which is described in M. Keshavarz-K. et al., Synthesis (1988) 641, with subsequent hydrolysis of the dimethylimmonio group to give the compound of the formula VIIIb which is then reacted with a compound of the formula VIII to give an intermediate of the formula VIb which upon hydrogenation to give a compound of the formula IVg and subsequent reaction with an amine of the formula V finally provides a compound of the formula I or Ia.

In the compounds of the formulae XXXVI, VIIb, VIb and IVg the group R³ is defined as in the compounds of the formulae I and Ia and, in addition, any functional groups can be present in protected form or in the form of precursor groups which are then converted into the desired final groups. The group R in the compounds of the formulae VIb and IVg is defined as in the compound of the formula IV and can thus be hydrogen, (C₁-C₄)-alkyl or benzyl, for example, where the formation of a compound of the formula VIb or IVg in which R is hydrogen may include an ester cleavage.

As applies to starting materials in processes for the preparation of compounds of the formulae I and Ia in general, the compounds of the formula XXXVI may also be employed in the form of salts, for example acid addition salts with hydrochloric acid. The reaction of the compound of the formula XXXVI or its salt with the compound of the formula XXXVII is generally carried out in a solvent, for example an alcohol like methanol or ethanol, an ether like THF, dioxane or DME, or an amide like DMF or NMP, in the presence of a base, for example an alkali metal alkoxide like sodium methoxide, sodium ethoxide or potassium tert-butoxide, at temperatures from about 20° C. to about 100° C. After treatment of the reaction mixture with water, the obtained aldehyde of the formula VIIIb is then with a compound of the formula VIII to give a compound of the formula VIb and the latter hydrogenated as outlined above.

Further compounds of the formulae I and Ia can be obtained from suitable intermediates or compounds of the formulae I and Ia prepared according to the above-described processes by functionalization or modification of contained functional groups according standard procedures, for example by esterification, amidation, hydrolysis, etherification, alkylation, acylation, sulfonylation, oxidation, reduction, conversion into salts, and others. As specific examples of oxidation reactions, the oxidation of ring nitrogen atoms to give N-oxides and the oxidation of sulfur atoms to give sulfoxides or sulfones may be mentioned, which are preferably carried out with hydrogen peroxide or a peracid such as 3-chloroperbenzoic acid.

All reactions used in the above-described syntheses of the compounds of the formulae I and Ia are per se well-known to the skilled person and can be carried out under standard conditions according, to or analogously to, procedures described in the literature, for example in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York. As already indicated above, depending on the circumstances of the individual case, in order to avoid an unwanted course of a reaction or side reactions during the synthesis of a compound, it can generally be necessary or advantageous to temporarily block functional groups by introducing protective groups and deprotect them at a later stage of the synthesis, or introduce functional groups in the form of precursor groups which later are converted into the desired functional groups. As examples of protecting groups, amino protecting groups such as the tert-butyloxycarbonyl group (Boc) which can be removed by treatment with trifluoroacetic acid (TFA), the benzyloxycarbonyl group which can be removed by catalytic hydrogenation, or the fluoren-9-ylmethoxycarbonyl group which can be removed by treatment with piperidine, carboxylic acid protecting groups such as the tert-butyl ester group which can be deprotected by treatment with TFA, or the benzyl ester group which can be deprotected by catalytic hydrogenation, or aldehyde and ketone protecting groups such as the dimethyl or diethyl acetal group and ketal group or the ethylene acetal group and ketal group which can be deprotected with dilute acid, may be mentioned. As an example of a precursor group the nitro group may be mentioned which can be converted into an amino group by reduction, for example by catalytic hydrogenation. Such synthesis strategies, and protective groups and precursor groups which are suitable in a specific case, are known to the skilled person. If desired, the obtained compounds of formulae I and Ia, as well as any intermediate compounds, can be purified by customary purification procedures, for example by recrystallization or chromatography.

The compounds of the formulae I and Ia are useful pharmacologically active, or pharmaceutically active compounds, which modulate the expression of endothelial NO synthase, and more specifically upregulate, or stimulate, the expression, or transcription, of endothelial NO synthase, and which can be employed as pharmaceuticals, or active ingredients of medicaments, for the treatment of various diseases. In the context of the present invention, treatment is understood as comprising both therapy, including alleviation and cure, of diseases and disease symptoms and prevention and prophylaxis of diseases and disease symptoms, such as, for example, the prevention of the appearance of asthmatic disease symptoms or the prevention of myocardial infarction or of myocardial reinfarction in affected patients. The diseases or disease symptoms can be acute or chronic. Diseases which can be treated with the compounds of the formulae I and Ia include, for example, cardiovascular diseases like stable and unstable angina pectoris, coronary heart disease, coronary artery disease, Prinzmetal angina (spasm), acute coronary syndrome, cardiac insufficiency, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease (=PAOD), endothelial dysfunction, atherosclerosis, restenosis, endothel damage after PTCA (=percutaneous transluminal coronary angioplasty), hypertension including essential hypertension, pulmonary hypertension and secondary hypertension (renovascular hypertension, chronic glomerulonephritis), erectile dysfunction, and ventricular arrhythmia. Further, the compounds of the formulae I and Ia can be used to lower the cardiovascular risk of postmenopausal women or after intake of contraceptives. Compounds of the formulae I and Ia can additionally be used in the treatment, including therapy and prevention, of diabetes and diabetes complications such as nephropathy or retinopathy, angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance or a restricted ability to learn. Preferred indications are stable angina pectoris, coronary heart disease, cardiac insufficiency, hypertension, endothelial dysfunction, atherosclerosis and diabetes complications.

The compounds of the formulae I and Ia can be used in combination with other pharmacologically active compounds or pharmaceuticals, preferably with compounds which are able to enhance the effect of the compounds according to the formulae I and Ia. Examples of such other compounds include statins; ACE inhibitors; AT1 antagonists; argininase inhibitors; PDE V inhibitors; calcium antagonists; alpha blockers; beta blockers; metimazol and analogous compounds; arginine; tetrahydrobiopterin; vitamins, in particular vitamin C and vitamin B6; niacine.

The compounds of the formulae I and Ia and their physiologically acceptable salts, optionally in combination with other pharmacologically active compounds, can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another, or in the form of pharmaceutical compositions. Further subjects of the present invention therefore also are the compounds of the formulae I and Ia and their physiologically acceptable salts for use as pharmaceuticals, their use as modulating agents, and more specifically as stimulating agents or upregulating agents, of the expression or transcription of endothelial NO synthase, for example in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level in a patient is desired, and in particular their use in the treatment, including therapy and prevention, of the above-mentioned diseases or syndromes, as well as their use for the preparation or manufacture of medicaments for these purposes.

Furthermore, a subject of the present invention are pharmaceutical compositions, or pharmaceutical preparations, which comprise at least one compound of the formulae I or Ia and/or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances and/or additives.

The pharmaceuticals according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously, for example in the form of solutions for injection or infusion. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred administration form depends, among others, on the disease to be treated and on its severity.

The amount of a compound of the formulae I or Ia and/or its physiologically acceptable salts present in the pharmaceutical compositions is chosen such that it is effective for the desired purpose, and normally ranges from about 0.2 to about 800 mg, preferably from about 0.5 to about 500 mg, in particular from about 1 to about 200 mg, per dose, but depending on the type of the pharmaceutical composition it may also be higher. The pharmaceutical compositions usually comprise from about 0.5 to about 90 percent by weight of the compounds of the formulae I or Ia and/or their physiologically acceptable salts. The production of the pharmaceutical compositions can be carried out in a manner known per se. To this end, one or more compounds of the formulae I or Ia and/or their physiologically acceptable salts together with one or more solid or liquid pharmaceutical carrier substances (or vehicles) and/or additives (or auxiliary substances) and, if a combination medicament is desired, other pharmacologically active compounds having therapeutic or prophylactic action are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules it is possible to use, for example, lactose, starch, for example maize starch, starch derivatives, talc, stearic acid or its salts, etc. Soft gelatin capsules and suppositories can comprise, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carrier substances for the preparation of solutions, for example of solutions for injection, or of emulsions or syrups are, for example, water, physiologically sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of the formulae I and Ia and their physiologically acceptable salts and to use the resulting lyophilisates, for example, for preparing compositions for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. Besides the compound or compounds according to the invention and carrier substances, the pharmaceutical compositions can also contain additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.

The dosage of the compound of the formulae I or Ia to be administered and/or of a physiologically acceptable salt thereof depends on the individual case and, as is customary, has to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compound used, on whether the use is for the therapy of an acute or chronic disease or prophylactic, or on whether other active compounds are administered in addition to compound of the formulae I or Ia. In general, a daily dose from about 0.01 mg/kg to about 100 mg/kg, preferably from about 0.1 mg/kg to about 10 mg/kg, in particular from about 0.3 mg/kg to about 5 mg/kg (in each case mg per kg of bodyweight) is appropriate for administration to an adult weighing about 75 kg in order to obtain the desired results. The daily dose can be administered in a single dose or, in particular when larger amounts are administered, divided into several, for example two, three or four individual doses. In some cases, depending on the individual response, it may be necessary to deviate upwards or downwards from the given daily dose.

The compounds of the formulae I and Ia can also be used for other purposes than those indicated in the foregoing. Non-limiting examples include the use as diagnostics, for example the use in methods for determining the activity of endothelial NO synthase in biological samples, the use as biochemical tools and the use as intermediates for the preparation of further compounds, for example further pharmacologically active compounds.

EXAMPLES

Compounds containing a basic group which were purified by preparative high pressure liquid chromatography (HPLC), specifically on reversed phase (RP) material, using an eluent which contained trifluoroacetic acid, were in part obtained in the form of acid addition salts with trifluoroacetic acid (TFA) which is not depicted in the formulae in the examples. The compounds were characterized by analytical HPLC and/or mass spectrometry (MS) and/or nuclear magnetic resonance spectrometry (NMR).

Example 1 3-[5-(4-Chloro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

(a) 3-(5-Bromo-thiophen-2-yl)-acrylic acid

3 g (15.7 mmol) of 5-Bromo-thiophene-2-carbaldehyde were dissolved in 30 ml of pyridine and 1.96 g (18.8 mmol) of malonic acid and 133 mg (1.6 mmol) of piperidine were added. The resulting solution was boiled under reflux for 6 h. The solution was cooled to room temperature and then poured into a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration, dissolved in ethyl acetate and washed with 0.1 M hydrochloric acid. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 3.0 g.

MS: m/e=234 (M+H)⁺

(b) 3-[5-(4-Chloro-phenyl)-thiophen-2-yl]-acrylic acid

0.250 g (1.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 61.9 mg (0.1 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 5 ml of degassed DME and stirred at room temperature for 10 min. 0.251 g (1.6 mmol) of 4-chlorophenylboronic acid and 1 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The resulting solution was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the resulting solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 0.12 g.

MS: m/e=265 (M+H)⁺

(c) 3-[5-(4-Chloro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propenone

0.12 g (0.5 mmol) of 3-[5-(4-chloro-phenyl)-thiophen-2-yl]-acrylic acid, 522 mg (4.5 mmol) of NEM and 163 mg (0.5 mmol) of TOTU were dissolved in 3 ml of DMF and stirred at room temperature for 15 min. Then 42.5 mg (0.5 mmol) of piperidine were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 72 mg.

MS: m/e=332 (M+H)⁺

(d) 3-[5-(4-Chloro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

10 mg of 5% palladium on carbon were added to a solution of 68 mg (0.2 mmol) of 3-[5-(4-chloro-phenyl)-thiophen-2-yl]-1-piperidin-1-yl-propenone in 5 ml of THF, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 4 h. The reaction mixture was filtered, evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 70 mg.

MS: m/e=334 (M+H)⁺

Example 2 2-[6-(2-Fluoro-phenyl)-pyridazin-3-yloxy]-1-(piperidin-1-yl)-ethanone

(a) 3-Bromo-6-(2-fluoro-phenyl)-pyridazine

300 mg (1.26 mmol) of 3,6-dibromopyridazine, 176.5 mg (1.26 mmol) 2-fluoro-phenylboronic acid, 34.7 mg (0.038 mmol) of tetrakis(triphenylphosphine)palladium and 1.26 ml of an aqueous 1 M sodium carbonate solution in 15 ml of DME were heated under reflux for 3 h. After cooling, the reaction mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried, evaporated, and the product purified by RP18 chromatography. Yield: 62 mg.

(b) [6-(2-Fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid tert-butyl ester

37.6 mg (0.285 mmol) of hydroxyacetic acid tert-butyl ester were dissolved in 10 ml of DMF, 12.4 mg of sodium hydride (55% in mineral oil) were added, and the mixture was stirred at room temperature for 15 min. Then 60 mg (0.237 mmol) of 3-bromo-6-(2-fluoro-phenyl)-pyridazine in 2 ml of DMF were added, and the reaction mixture was stirred at 60° C. for 5 h and at 120° C. for 5 h. After evaporation to dryness, the crude product was directly employed in the subsequent step.

(c) [6-(2-Fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid

To the crude [6-(2-fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid tert-butyl ester obtained in step (b) 5 ml of 90% aqueous TFA were added, and the mixture was allowed to stand at room temperature overnight. After evaporation, a sodium hydrogencarbonate solution was added, and the solution extracted with ethyl acetate. The aqueous phase was acidified to pH=4 and extracted with ethyl acetate. The combined extracts were dried and evaporated. Yield: 20 mg.

(d) 2-[6-(2-Fluoro-phenyl)-pyridazin-3-yloxy]-1-(piperidin-1-yl)-ethanone

20 mg (0.08 mmol) of [6-(2-fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid, 10.3 mg (0.12 mmol) of piperidine, 27.8 mmol (0.24 mmol) of NEM and 29.1 mg (0.089 mmol) of TOTU in THF were stirred at room temperature for 3 h. After filtration and evaporation, the product was purified by RP18 chromatography. Yield: 7 mg.

MS: m/e=316 (M+H)⁺

Example 3 2-[6-(4-Fluoro-phenyl)-pyridazin-3-yloxy]-(1-piperidin-1-yl)-ethanone

(a) (6-Bromo-pyridazin-3-yloxy)-acetic acid tert-butyl ester

277.8 mg (2.1 mmol) of hydroxyacetic acid tert-butyl ester and 100.9 mg of sodium hydride (55% in mineral oil) in 15 ml of DMF were stirred at room temperature for 30 min. Then 500 mg (2.1 mmol) of 3,6-dibromopyridazine were added, and the reaction mixture was stirred at 60° C. for 2 h. After evaporation to dryness, the residue was stirred with ethyl acetate, the solution filtered, evaporated, and the crude product (450 mg) directly employed in the subsequent step.

(b) (6-Bromo-pyridazin-3-yloxy)-acetic acid

To the crude (6-bromo-pyridazin-3-yloxy)-acetic acid tert-butyl ester obtained in step (a) 5 ml of 90% aqueous TFA were added, and the mixture was allowed to stand at room temperature for 3 h. After evaporation, a sodium hydrogencarbonate solution was added, and the solution extracted with ethyl acetate. The aqueous phase was acidified to pH=4 and extracted with ethyl acetate. The combined extracts were dried and evaporated. Yield: 147 mg.

(c) 2-(6-Bromo-pyridazin-3-yloxy)-(1-piperidin-1-yl)-ethanone

146 mg (0.626 mmol) of (6-bromo-pyridazin-3-yloxy)-acetic acid, 216.5 mg (1.88 mmol) of NEM and 226 mg (0.689 mmol) of TOTU in 10 ml of THF were stirred at room temperature for 15 min, 80 mg (0.94 mmol) of piperidine added, and the reaction mixture stirred at room temperature for 3 h. After evaporation, a sodium hydrogencarbonate solution and ethyl acetate were added to the residue, and the organic phase was separated, washed, dried and evaporated. Yield: 190 mg.

(d) 2-[6-(4-Fluoro-phenyl)-pyridazin-3-yloxy]-(1-piperidin-1-yl)-ethanone

95 mg (0.326 mmol) of 2-(6-bromo-pyridazin-3-yloxy)-(1-piperidin-1-yl)-ethanone, 46.7 mg (0.334 mmol) 4-fluoro-phenylboronic acid, 11 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium and 0.5 ml of a 1 M aqueous sodium carbonate solution in 15 ml of DME were heated under reflux for 3 h. After cooling, the mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated, and the product was purified by RP18 chromatography. Yield: 73 mg.

MS: m/e=316 (M+H)⁺

Example 4 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-(1-piperidin-1-yl)-propan-1-one

(a) 3-(5-Bromo-thiophen-2-yl)-(1-piperidin-1-yl)-propenone

0.50 g (2.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid, 2.47 g (21.5 mmol) of NEM and 774 mg (2.4 mmol) of TOTU were dissolved in 5 ml of DMF and the mixture stirred at room temperature for 15 min. 201 mg (0.5 mmol) of piperidine were added, and the reaction mixture stirred at room temperature for 16 h. After evaporation of the solvent under reduced pressure, the product was purified by silica gel chromatography. Yield: 458 mg.

MS: m/e=300 (M)⁺

(b) 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-(1-piperidin-1-yl)-propenone

0.250 g (0.8 mmol) of 3-(5-bromo-thiophen-2-yl)-(1-piperidin-1-yl)-propenone and 48.1 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 5 ml of degassed DME and the mixture stirred at room temperature for 10 min. 0.251 g (1.6 mmol) of 4-fluoro-phenylboronic acid and 1 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The resulting mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the resulting solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent removed under reduced pressure. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 120 mg.

MS: m/e=316 (M)⁺

(c) 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

50 mg of 5% palladium on carbon were added to a solution of 105 mg (0.3 mmol) of 3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propenone in 15 ml of tetrahydrofuran, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 12 h. The reaction mixture was filtered, evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 90 mg.

MS: m/e=318 (M+H)⁺

Example 5 1-(4-Acetyl-piperazin-1-yl)-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propan-1-one

(a) 3-[5-(4-Trifluoromethoxy-phenyl)-thiophen-2-yl]-acrylic acid

0.72 g (3.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 178.3 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 0.954 g (4.6 mmol) of 4-trifluoromethoxy-phenylboronic acid and 3 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 426 mg.

MS: m/e=315 (M+H)⁺

(b) 3-[5-(4-Trifluoromethoxy-phenyl)-thiophen-2-yl]-propionic acid

40 mg of 5% palladium on carbon were added to a solution of 416 mg (1.3 mmol) of 3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-acrylic acid in 20 ml of THF, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 24 h. Then 10 ml of methanol and 40 mg of 5% palladium on carbon were added, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for further 24 hours. Then 10 ml of acetic acid were added, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for another 24 h. The mixture was filtered and evaporated under reduced pressure. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 400 mg.

MS: m/e=317 (M+H)⁺

(c) 1-(4-Acetyl-piperazin-1-yl)-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propan-1-one

50 mg (0.16 mmol) of 3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propionic acid, 0.182 g (1.58 mmol) of NEM and 57 mg (0.17 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 22 mg (0.17 mmol) of 1-acetyl-piperazine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 17 mg.

MS: m/e=427 (M+H)⁺

Example 6 1-(4-Pyrimidin-2-yl-piperazin-1-yl)-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propan-1-one

The title compound was prepared analogously as described in Example 5(c). Yield: 26 mg.

MS: m/e=463 (M+H)⁺

Example 7 N-Cyclopropylmethyl-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propionamide

The title compound was prepared analogously as described in Example 5(c). Yield: 15 mg.

MS: m/e=370 (M+H)⁺

Example 8 N-(2,2,2-Trifluoro-ethyl)-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propionamide

The title compound was prepared analogously as described in Example 5(c). Yield: 20 mg.

MS: m/e=398 (M+H)⁺

Example 9 1-(4-Phenyl-piperazin-1-yl)-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propan-1-one

The title compound was prepared analogously as described in Example 5(c). Yield: 25 mg.

MS: m/e=461 (M+H)⁺

Example 10 N-Phenyl-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propionamide

The title compound was prepared analogously as described in Example 5(c). Yield: 22 mg.

MS: m/e=392 (M+H)⁺

Example 11 N-Cyclohexyl-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propionamide

The title compound was prepared analogously as described in Example 5(c). Yield: 22 mg.

MS: m/e=398 (M+H)⁺

Example 12 1-(Piperidin-1-yl)-3-[5-(4-trifluoromethoxy-phenyl)-thiophen-2-yl]-propan-1-one

The title compound was prepared analogously as described in Example 5(c). Yield: 25 mg.

MS: m/e=384 (M+H)⁺

Example 13 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-(4-methyl-piperazin-1-yl)-propan-1-one trifluoroacetic acid salt

(a) 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-acrylic acid

1 g (4.3 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 247 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 0.900 g (6.4 mmol) of 4-fluoro-phenylboronic acid and 4 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. Yield: 500 mg.

MS: m/e=249 (M+H)⁺

(b) 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-propionic acid

40 mg of 5% palladium on carbon were added to a solution of 500 mg (2.0 mmol) of 3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-acrylic acid in 20 ml of tetrahydrofuran, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 24 h. 10 ml of methanol and 40 mg of 5% palladium on carbon were added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for further 24 hours. 10 ml of acetic acid were added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for another 24 h. The mixture was filtered and evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 400 mg.

MS: m/e=251 (M+H)⁺

(c) 3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-(4-methyl-piperazin-1-yl)-propan-1-one trifluoroacetic acid salt

50 mg (0.2 mmol) of 3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-propionic acid, 0.633 g (5.5 mmol) of NEM and 180 mg (0.55 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 50 mg (0.5 mmol) of 1-methyl-piperazine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 45 mg.

MS: m/e=333 (M+H)⁺

Example 14 4-{3-[5-(4-Fluoro-phenyl)-thiophen-2-yl]-propionyl}-piperazin-2-one

The title compound was prepared analogously as described in Example 13(c). Yield: 40 mg.

MS: m/e=333 (M+H)⁺

Example 15 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

(a) 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-acrylic acid

9.38 g (40.2 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 6.97 g (6 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 50 ml of degassed DME and stirred at room temperature for 10 min. 8.44 g (60.4 mmol) of 2-fluoro-phenylboronic acid and 50 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. The product precipitated partially from the reaction mixture and was collected by filtration. This solid was boiled for 1 h in ethyl acetate and filtered while hot. The solvent was removed under reduced pressure. The filtrate of the reaction mixture was evaporated to dryness. This residue was taken up in ethyl acetate/water and filtered. The organic phase was dried with sodium sulfate, filtered, and the solvent was evaporated. The combined product was purified by silica gel chromatography. Yield: 7.5 g.

MS: m/e=249 (M+H)⁺

(b) 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propenone

0.21 g (0.8 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-acrylic acid, 965 mg (8.4 mmol) of NEM and 302 mg (0.9 mmol) of TOTU were dissolved in 3 ml of DMF and stirred at room temperature for 15 min. 78.5 mg (0.9 mmol) of piperidine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 65 mg.

MS: m/e=316 (M+H)⁺

(c) 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

5 mg of 5% palladium on carbon were added to a solution of 49 mg (0.2 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-1-piperidin-1-yl-propenone in 10 ml of THF, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 16 hours. The mixture was filtered and evaporated under reduced pressure. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 39 mg.

MS: m/e=318 (M+H)⁺

Example 16 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-one trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 15 using 100 mg of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-1-(4-methyl-piperazin-1-yl)-propenone in step (c). Yield: 72 mg.

MS: m/e=333 (M+H)⁺

Example 17 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-one

The title compound was prepared analogously as described in Example 15 using 100 mg of 4-{3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-acryloyl}-piperazin-2-one in step (c). Yield: 65 mg.

MS: m/e=333 (M+H)⁺

Example 18 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-N-(pyridin-4-yl)-propionamide trifluoroacetic acid salt

(c) 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-propionic acid methyl ester

100 mg of 5% palladium on carbon were added to a solution of 5 g (20.1 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-acrylic acid in 200 ml of methanol, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 7 days. The mixture was filtered and evaporated. The product was purified by silica gel chromatography. Yield: 2.9 g.

MS: m/e=265 (M+H)⁺

(b) 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-propionic acid

500 mg (1.9 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-propionic acid methyl ester was dissolved in 5 ml of dioxane and 5 ml of a 2 N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 16 h, diluted with water and acidified to pH=2 by the addition of concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 398 mg.

MS: m/e=251 (M+H)⁺

(c) 3-[5-(2-Fluoro-phenyl)-thiophen-2-yl]-N-(pyridin-4-yl)-propionamide trifluoroacetic acid salt

50 mg (0.2 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-propionic acid, 230 mg (2 mmol) of NEM and 72 mg (0.22 mmol) of TOTU were dissolved in 3 ml of DMF and stirred at room temperature for 15 min. 18.8 mg (0.2 mmol) of pyridin-4-ylamine were added, and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered and evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 3.3 mg.

MS: m/e=327 (M+H)⁺

Example 19 N-Cyclohexyl-3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-propionamide

The title compound was prepared analogously as described in Example 18(b). Yield: 50 mg.

MS: m/e=332 (M+H)⁺

Example 20 1-(4-Acetyl-piperazin-1-yl)-3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-propan-1-one

The title compound was prepared analogously as described in Example 18(b). Yield: 57 mg.

MS: m/e=361 (M+H)⁺

Example 21 1-(Piperidin-1-yl)-2-(4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-ethanone trifluoroacetic acid salt

(a) (4-(Pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid tert-butyl ester

150 mg (0.534 mmol) 2-Bromo-1-(pyridin-3-yl)-ethanone hydrobromide, 144.8 mg (0.534 mmol) of carbamimidoylsulfanyl-acetic acid tert-butyl ester hydrobromide and 207 mg (1.6 mmol) of diisopropylethylamine in 5 ml of acetonitrile were stirred at room temperature for 3 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 34 mg.

MS: m/e=292 (M+H)⁺

(b) (4-(Pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid trifluoroacetic acid salt

30 mg (0.1 mmol) of (4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid tert-butyl ester were allowed to stand in 1 ml of 90% aqueous TFA at room temperature for 1 h. The mixture was evaporated, and the product employed in the subsequent step without further purification. Yield: 33 mg.

(c) 1-(Piperidin-1-yl)-2-(4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-ethanone trifluoroacetic acid salt

32 mg (0.069 mmol) of (4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid trifluoroacetic acid salt from step (b), 8.8 mg (0.1 mmol) of piperidine, 24.9 mg (0.076 mmol) TOTU and 15.9 mg (0.138 mmol) NEM in 4 ml of DMF were stirred at room temperature for 4 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 7 mg.

MS: m/e=303 (M+H)⁺

Example 22 4-[3-(6-Phenoxy-pyridin-3-yl)-propionyl]-piperazin-2-one

(a) 3-(6-Phenoxy-pyridin-3-yl)-acrylic acid

5 g (25.1 mmol) of 6-phenoxy-pyridine-3-carbaldehyde were dissolved in 50 ml of pyridine, and 3.134 g (30.1 mmol) of malonic acid and 213 mg (2.5 mmol) of piperidine were added. The reaction mixture was boiled under reflux for 6 h. After cooling to room temperature, it was poured into a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 5.66 g.

MS: m/e=242 (M+H)⁺

(b) 4-[3-(6-Phenoxy-pyridin-3-yl)-acryloyl]-piperazin-2-one

0.15 g (0.62 mmol) of 3-(6-phenoxy-pyridin-3-yl)-acrylic acid, 1.72 g (15 mmol) of NEM and 546 mg (1.6 mmol) of TOTU were dissolved in 5 ml of DMF and stirred at room temperature for 15 min. 163 mg (1.626 mmol) of piperazin-2-one were added and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by silica gel chromatography. Yield: 153 mg.

MS: m/e=324 (M+H)⁺

(c) 4-[3-(6-Phenoxy-pyridin-3-yl)-propionyl]-piperazin-2-one

10 mg of 5% palladium on carbon were added to a solution of 142 mg (0.4 mmol) of 4-[3-(6-phenoxy-pyridin-3-yl)-acryloyl]-piperazin-2-one in 15 ml of methanol, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 12 h. The mixture was filtered and evaporated. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 87 mg.

MS: m/e=326 (M+H)⁺

Example 23 3-[2,2′]Bithiophenyl-5-yl-1-piperidin-1-yl-propan-1-one

The title compound was prepared analogously as described in Example 22(b) and (c) by hydrogenation of 3-[2,2′]bithiophenyl-5-yl-1-(piperidin-1-yl)-propenone (MS: m/e=304 (M+H)⁺), which had been obtained in a yield of 65 mg from 3-[2,2′]bithiophenyl-5-yl-acrylic acid. Yield: 91 mg.

MS: m/e=306 (M+H)⁺

Example 24 5-(3-Oxo-3-(piperidin-1-yl)-propyl)-3-phenyl-3H-[1,3,4]oxadiazol-2-one

(a) 3-(N′-Phenyl-hydrazinocarbonyl)-propionic acid

2.5 g (23 mmol) of phenylhydrazine were dissolved in 30 ml of dichloromethane and 2.3 g (23 mmol) of succinic anhydride were added portionwise. The reaction mixture was stirred at room temperature for 16 h. The precipitated product was isolated by filtration and washed with dichloromethane. Yield: 4.2 g.

MS: m/e=209 (M+H)⁺

(b) 3-(5-Oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-propionic acid

500 mg (2.4 mmol) of 3-(N′-phenyl-hydrazinocarbonyl)-propionic acid were dissolved in 10 ml of THF and 213 mg (0.7 mmol) of triphosgene were added. The reaction mixture was stirred at room temperature overnight. Then a saturated sodium hydrogencarbonate solution was added, and the mixture was evaporated to dryness under reduced pressure. The residue was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 315 mg.

MS: m/e=235 (M+H)⁺

(c) 5-(3-Oxo-3-(piperidin-1-yl)-propyl)-3-phenyl-3H-[1,3,4]oxadiazol-2-one

50 mg (0.21 mmol) of 3-(5-oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-propionic acid, 245 mg (2.13 mmol) of NEM and 77 mg (0.23 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 20 mg (0.23 mmol) of piperidine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by silica gel chromatography. Yield: 45 mg.

MS: m/e=302 (M+H)⁺

Example 25 5-[3-(4-Acetyl-piperazin-1-yl)-3-oxo-propyl]-3-phenyl-3H-[1,3,4]oxadiazol-2-one

The title compound was prepared analogously as described in Example 24(c). Yield: 38 mg.

MS: m/e=345 (M+H)⁺

Example 26 3-(5-Oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-N-phenyl-propionamide

The title compound was prepared analogously as described in Example 24(c). Yield: 48 mg.

MS: m/e=310 (M+H)⁺

Example 27 4-[3-(5-Oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-propionyl]-piperazin-2-one

The title compound was prepared analogously as described in Example 24(c). Yield: 41 mg.

MS: m/e=317 (M+H)⁺

Example 28 2-[5-(2-Fluoro-phenyl)-pyrimidin-2-yloxy]-1-(piperidin-1-yl)-ethanone

(a) (5-Bromo-pyrimidin-2-yloxy)-acetic acid tert-butyl ester

137 mg of sodium hydride (55% in mineral oil) were added to 500 mg (2.86 mmol) of 5-bromo-pyrimidin-2-ol in 20 ml of DMF, and the mixture was stirred at room temperature for 15 min. Then 613 mg (3.14 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 1 h. After addition of water, the mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give the crude product. Yield: 868 mg.

(b) [5-(2-Fluoro-phenyl)-pyrimidin-2-yloxy]-acetic acid tert-butyl ester

500 mg (1.73 mmol) of (5-bromo-pyrimidin-2-yloxy)-acetic acid tert-butyl ester from step (a), 190.4 mg (2.07 mmol) of 2-fluorophenylboronic acid, 19.4 mg (0.086 mmol) of palladium acetate, 45.4 mg (0.17 mmol) of triphenylphosphine and 1.07 ml of an aqueous 1 M sodium carbonate solution in 40 ml of toluene were heated under reflux for 8 h. After cooling, the mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. Yield: 335 mg.

(c) [5-(2-Fluoro-phenyl)-pyrimidin-2-yloxy]-acetic acid

335 mg (1.1 mmol) of [5-(2-fluoro-phenyl)-pyrimidin-2-yloxy]-acetic acid tert-butyl ester in 10 ml of 90% aqueous TFA were allowed to stand at room temperature for 3 h. After evaporation, a sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The aqueous phase was acidified to pH=4, extracted with ethyl acetate, and the combined organic phases were dried and evaporated. Yield: 51 mg.

(d) 2-[5-(2-Fluoro-phenyl)-pyrimidin-2-yloxy]-1-(piperidin-1-yl)-ethanone

50 mg (0.2 mmol) [of 5-(2-fluoro-phenyl)-pyrimidin-2-yloxy]-acetic acid, 34.3 mg (0.4 mmol) of piperidine, 84.3 mg (0.22 mmol) of HATU and 61.2 mg (0.6 mmol) of triethylamine in 5 ml of DMF were stirred at room temperature for 4 h. After evaporation, ethyl acetate and a potassium carbonate solution were added, the organic phase was separated, washed with water, dried and evaporated. The product was purified by RP18 chromatography. Yield: 7.5 mg.

MS: m/e=316 (M+H)⁺

Example 29 3-Methyl-1-(piperidin-1-yl)-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butan-1-one

(a) 3-Methyl-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butyric acid ethyl ester

500 mg (1.99 mmol) of 5-bromo-3,3-dimethyl-4-oxo-pentanoic acid ethyl ester, 408.6 mg (1.99 mmol) of 4-trifluoromethyl-thiobenzamide and 403 mg (3.98 mmol) of triethylamine in 10 ml of toluene were stirred at 80° C. for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 8:1). Yield: 498.5 mg.

MS: m/e=358 (M+H)⁺

(b) 3-Methyl-1-(piperidin-1-yl)-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butan-1-one

27.5 mg (0.63 mmol) of sodium hydride (55% in mineral oil) were added to 53.6 mg (0.63 mmol) of piperidine in 2 ml of DMF. After stirring at room temperature for 30 min, 150 mg (0.42 mmol) of 3-methyl-3-[2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-butyric acid ethyl ester in 2 ml of DMF were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, and evaporated. The product was purified by RP18 chromatography. Yield: 6.3 mg.

MS: m/e=397 (M+H)⁺

Example 30 2-[4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-1-(piperidin-1-yl-ethanone

(a) 4-(4-Fluoro-phenyl)-thiazol-2-ol

1.085 g (5 mmol) of 2-bromo-1-(4-fluoro-phenyl)-ethanone and 405 mg (5 mmol) of sodium thiocyanate in 40 ml of ethanol were heated under reflux for 30 min. Then 20 ml of ethanol were distilled off, water was added, the precipitate was filtered off, 10 ml of acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulfuric acid were added, and the mixture was stirred at 100° C. for 1 h. After dilution with water, the precipitated product was filtered off, washed with water and dried. Yield: 782 mg.

MS: m/e=195 (M+H)⁺

(b) [4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-acetic acid tert-butyl ester

123 mg (2.82 mmol) of sodium hydride (55% in mineral oil) were added to 500 mg (2.56 mmol) of 4-(4-fluoro-phenyl)-thiazol-2-ol in 15 ml of DMF. After stirring at room temperature for 30 min, 549.6 mg (2.82 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated to give 762 mg of a mixture of title compound and N-alkylated product.

(c) [4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt

The mixture from step (b) containing crude [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid tert-butyl ester in 5 ml of 90% aqueous TFA was allowed to stand at room temperature for 2 h. After evaporation, the crude product (815 mg) was used in the subsequent step.

(d) 2-[4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-1-(piperidin-1-yl-ethanone

114.7 mg (0.31 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt from step (c), 53.2 mg (0.62 mmol) of piperidine, 118.8 mg (0.31 mmol) of HATU and 94.8 mg (0.94 mmol) of triethylamine in 8 ml of DMF were stirred at room temperature for 2 h. After evaporation, a sodium hydrogencarbonate solution and ethyl acetate were added, the organic phase was separated, washed with water, dried and evaporated. The product was purified by RP18 chromatography. Yield: 45 mg.

MS: m/e=321 (M+H)⁺

Example 31 N-Cyclopropyl-2-[4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetamide

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 31.1 mg (0.54 mmol) of cyclopropylamine. Yield: 21.5 mg.

MS: m/e=293 (M+H)⁺

Example 32 2-[4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-N-phenyl-acetamide

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 50.7 mg (0.54 mmol) of aniline. Yield: 7.6 mg.

MS: m/e=329 (M+H)⁺

Example 33 2-[4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-1-(pyrrolidin-1-yl)-ethanone

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 38.7 mg (0.54 mmol) of pyrrolidine. Yield: 6 mg.

MS: m/e=307 (M+H)⁺

Example 34 1-(Azetidin-1)-yl-2-[4-(4-fluoro-phenyl)-thiazol-2-yloxy]-ethanone

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 31.1 mg (0.54 mmol) of pyrrolidine. Yield: 5 mg.

MS: m/e=293 (M+H)⁺

Example 35 2-[4-(4-Fluoro-phenyl)-thiazol-2-yloxy]-N-(thiazol-2-yl)-acetamide

The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.24 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 47 mg (0.47 mmol) of 2-amino-thiazole. Yield: 5 mg.

MS: m/e=336 (M+H)⁺

Example 36 General Procedure 1: Preparation of N-substituted 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionamides of the formula If

(a) 5-Bromo-2-(2-fluoro-phenyl)-pyridine

Under nitrogen, 39.2 g (0.28 mol) of 2-fluoro-phenylboronic acid, 59.9 g (0.25 mol) of 2,5-dibromopyridine and 2.17 g of tetrakis(triphenylphosphine)palladium were dissolved in 420 ml of ethanol and 840 ml of toluene. 840 ml of a 2 N sodium carbonate solution were added, and the mixture heated to 80° C. for 1 h. Afterwards the mixture was cooled to 5 to 10° C., 800 ml of ethyl acetate were added, and the precipitated salts were separated by filtration. The organic phase of the mother liquor was separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness.

The remaining solid was purified via chromatography (silica gel, n-heptane/ethyl acetate 5:1). Yield: 42.1 g.

MS: m/e=253 (M+H)⁺

(b) 3-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-acrylic acid ethyl ester

Under nitrogen, 0.755 g (3.38 mmol) of palladium acetate, 2.05 g (6.75 mmol) of tri(ortho-tolyl)phosphine and 97.8 ml (0.708 mol) of triethylamine were added to a solution of 34.0 g (0.135 mol) of 5-bromo-2-(2-fluoro-phenyl)-pyridine in 2.2 l of acetonitrile. Then 23.38 ml (0.216 mol) of acrylic acid ethyl ester were added, and the mixture was shaken in an autoclave at 125° C. for 20 h. After cooling, the mixture was poured onto ice/water, the mixture stirred at 5 to 10° C. for 1 h, and the precipitated product was collected by filtration and purified by chromatography (silica gel, n-heptane/ethyl acetate 3:1). Yield: 24.3 g.

Melting point: 73 to 74° C. MS: m/e=272 (M+H)⁺

(c) 3-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-propionic acid ethyl ester

Under nitrogen, 16.26 g (0.06 mol) of 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-acrylic acid ethyl ester were dissolved in 500 ml of 95% ethanol and cooled to 5 to 10° C. After addition of 9.42 g (0.03 mol) of bismuth trichloride, a total of 9.12 g (0.24 mol) of sodium borohydride was added in portions over 45 min. The resulting mixture was stirred at 15 to 20° C. for 1 h, then cooled to 10° C. and poured onto ice/water. The pH was adjusted to 7 with 2 N hydrochloric acid, dichloromethane was added, and the precipitated salts were separated by filtration. The organic phase of the mother liquor was separated, and the aqueous phase extracted once with dichloromethane. The combined organic phases were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The remaining solid was purified by chromatography (silica gel, n-heptane/ethyl acetate 3:1). Yield: 11.5 g.

MS: m/e=274 (M+H)⁺

(d) 3-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-propionic acid

11.5 g (0.042 mol) of 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionic acid ethyl ester were dissolved in 230 ml ethanol, 7.7 ml of a 32% sodium hydroxide solution were added, and the mixture stirred at 45 to 50° C. for 1 h. After evaporation to dryness, the remaining solid was taken up in 100 ml of water, the pH was adjusted to 2.5 to 3 with 2 N hydrochloric acid, and the precipitated product was filtered off with suction. The solid was rinsed with water and dried. Yield 10.0 g.

Melting point: 83 to 84° C. MS: m/e=246 (M+H)⁺

(e) 3-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-propionyl chloride hydrochloride

The title compound was prepared in quantitative yield by boiling 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionic acid in thionyl chloride, followed by removal of the volatiles by coevaporating three times with toluene.

(f) Preparation of N-substituted 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionamides

3-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-propionyl chloride hydrochloride was dissolved in pyridine, and 1 equivalent of the respective amine was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and residual pyridine was removed by coevaporating three times with toluene. The residue was dissolved in DMF, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid.

According to general procedure 1, the example compounds of the formula If listed in Table 1 were prepared which were obtained in the form of their trifluoroacetic acid salts. The compounds may be named as N-substituted 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionamide trifluoroacetic acid salt, for example as 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-N-(thiophen-2-yl-methyl)-propionamide trifluoroacetic acid salt in the case of Example 65, or as 1-substituted 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propan-1-one trifluoroacetic acid salt, for example as 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-1-(pyrrolidin-1-yl)-propan-1-one trifluoroacetic acid salt in the case of Example 51, or in another manner, for example as 1-{3-[6-(2-fluoro-phenyl]-pyridin-3-yl]-propionoyl}-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetic acid salt in the case of Example 55, depending on the structure of the individual compound.

TABLE 1 Example compounds of the formula If Example No.

MS: m/e = 37

355 (M + H)⁺ 38

389 (M + H)⁺ 39

389 (M + H)⁺ 40

389 (M + H)⁺ 41

357 (M + H)⁺ 42

355 (M + H)⁺ 43

339 (M + H)⁺ 44

357 (M + H)⁺ 45

352 (M + H)⁺ 46

322 (M + H)⁺ 47

401 (M + H)⁺ 48

335 (M + H)⁺ 49

328 (M + H)⁺ 50

285 (M + H)⁺ 51

299 (M + H)⁺ 52

315 (M + H)⁺ 53

343 (M + H)⁺ 54

329 (M + H)⁺ 55

357 (M + H)⁺ 56

317 (M + H)⁺ 57

301 (M + H)⁺ 58

361 (M + H)⁺ 59

273 (M + H)⁺ 60

299 (M + H)⁺ 61

301 (M + H)⁺ 62

287 (M + H)⁺ 63

349 (M + H)⁺ 64

336 (M + H)⁺ 65

341 (M + H)⁺ 66

349 (M + H)⁺

Example 67 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

(a) [4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-acetic acid tert-butyl ester

2 g (9.2 mmol) of 2-bromo-1-(4-fluoro-phenyl)-ethanone and 801.7 mg (9.89 mmol) of sodium thiocyanate in 25 ml of ethanol were stirred at 50° C. for 4 h. 1.2 g (9.2 mmol) of aminoacetic acid tert-butyl ester in 2.5 ml of ethanol were added, and the reaction mixture was stirred at room temperature for 2.5 h and allowed to stand overnight. After evaporation, water and ethyl acetate were added, the organic phase was separated, washed with water, dried and evaporated. Yield: 787 mg.

MS: m/e=309 (M+H)⁺

(b) [4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt

780 mg (2.53 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid tert-butyl ester in 10 ml of 90% aqueous TFA were allowed to stand at room temperature for 3 h. The mixture was concentrated and lyophilized. Yield: 859 mg.

(c) 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 46.5 mg (0.54 mmol) of piperidine. Yield: 58 mg.

MS: m/e=320 (M+H)⁺

Example 68 1-(Azetidin-1-yl)-2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 31.2 mg (0.54 mmol) of azetidine. Yield: 27 mg.

MS: m/e=292 (M+H)⁺

Example 69 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-1-(pyrrolidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 38.8 mg (0.54 mmol) of pyrrolidine. Yield: 17 mg.

MS: m/e=306 (M+H)⁺

Example 70 N-Cyclopropyl-2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 31.2 mg (0.54 mmol) of cyclopropylamine. Yield: 53 mg.

MS: m/e=292 (M+H)⁺

Example 71 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-N-phenyl-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 50.8 mg (0.54 mmol) of aniline. Yield: 4.7 mg.

MS: m/e=328 (M+H)⁺

Example 72 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-N,N-dimethyl-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt, 66.8 mg (0.81 mmol) of dimethylamine hydrochloride and 165.7 mg (1.64 mmol) of triethylamine. Yield: 52 mg.

MS: m/e=280 (M+H)⁺

Example 73 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-N-thiazol-2-yl-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 200 mg (0.55 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 109.4 mg (1.1 mmol) of 2-aminothiazole. Yield: 3.3 mg.

MS: m/e=335 (M+H)⁺

Example 74 N-(4-Fluoro-phenyl)-2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 200 mg (0.55 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 121.3 mg (1.1 mmol) of 4-fluoroaniline. Yield: 13 mg.

MS: m/e=346 (M+H)⁺

Example 75 N-tert-Butyl-2-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 39.9 mg (0.55 mmol) of tert-butylamine. Yield: 15 mg.

MS: m/e=308 (M+H)⁺

Example 76 2-[6-(2-Fluoro-phenyl)-pyridin-3-yloxy]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

(a) 2-(2-Fluoro-phenyl)-5-nitro-pyridine

5 g (24.6 mmol) of 2-bromo-5-nitro-pyridine, 3.79 g (27.1 mmol) of 2-fluoro-phenylboronic acid, 276.5 mg (1.23 mmol) of palladium acetate, 646 mg (2.46 mmol) of triphenylphosphine and 24.6 ml of a 1 M aqueous sodium carbonate solution in 150 ml of toluene and 37 ml of ethanol were heated under reflux for 5 h. After cooling, the mixture concentrated under reduced pressure to half of its volume, poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The product was purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). Yield: 4.2 g.

(b) 6-(2-Fluoro-phenyl)-pyridin-3-ylamine

50 mg of 10% palladium on carbon were added to a solution of 3.2 g (14.66 mmol) of 2-(2-fluoro-phenyl)-5-nitro-pyridine in 250 ml of ethanol, and the reaction mixture was hydrogenated at atmospheric pressure for 3 h. After filtration, the solution was evaporated. Yield: 2.5 g.

MS: m/e=189 (M+H)⁺

(c) 6-(2-Fluoro-phenyl)-pyridin-3-ol

3.3 ml (26.6 mmol) of boron trifluoride diethylether complex were cooled to −15° C. Then 2.5 g (13.3 mmol) of 6-(2-fluoro-phenyl)-pyridin-3-ylamine in 5 ml of DME and, subsequently, 1.9 ml (15.9 mmol) of tert-butyl nitrite were added dropwise. Shortly after, a thick precipitate formed. The mixture was diluted with 8 ml of DME and 8 ml of dichloromethane and stirred in an ice bath for 2 h. After addition of 50 ml of pentane, the precipitate was filtered off, dried, and stirred in 50 ml of acetic anhydride at 100° C. for 1 h. After concentration, a sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue was purified by chromatography (silica gel, n-heptane/ethyl acetate 5:1). The obtained product was stirred with a 15% aqueous potassium hydroxide solution and few methanol in an ice bath and subsequently for 2 h at room temperature. After neutralization with 2 N hydrochloric acid, the mixture was extracted with ethyl acetate, and the combined extracts were dried and evaporated. Yield: 871 mg.

MS: m/e=190 (M+H)⁺

(d) [6-(2-Fluoro-phenyl)-pyridin-3-yloxy]-acetic acid tert-butyl ester

Under argon, 63.4 mg (1.45 mmol) of sodium hydride (55% in mineral oil) were added to 250 mg (1.32 mmol) of 6-(2-fluoro-phenyl)-pyridin-3-ol in 10 ml of DMF. The mixture was stirred at room temperature for 60 min. Then 283.5 mg (1.45 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After evaporation, water was added, and the mixture was extracted with ethyl acetate. The combined extracts were dried and concentrated. Yield: 311 mg.

MS: m/e=304 (M+H)⁺

(e) [6-(2-Fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt

300 mg (0.99 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid tert-butyl ester in 10 ml of 90% aqueous TFA were allowed to stand at room temperature for 1.5 h. The mixture was concentrated and lyophilized. Yield: 286 mg.

MS: m/e=248 (M+H)⁺

(f) 2-[6-(2-Fluoro-phenyl)-pyridin-3-yloxy]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.277 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 47.1 mg (0.554 mmol) of piperidine. Yield: 72 mg.

MS: m/e=315 (M+H)⁺

Example 77 2-[6-(2-Fluoro-phenyl)-pyridin-3-yloxy]-N-(pyridin-2-yl)-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.25 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 28.1 mg (0.3 mmol) of 2-aminopyridine. Yield: 28 mg.

MS: m/e=324 (M+H)⁺

Example 78 2-[6-(2-Fluoro-phenyl)-pyridin-3-yloxy]-N-(thiazol-2-yl)-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.25 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 29.9 mg (0.3 mmol) of 2-aminothiazole. Yield: 16 mg.

MS: m/e=330 (M+H)⁺

Example 79 3-(6-Amino-5-phenyl-pyridin-2-yl)-1-(piperidin-1-yl)-propanone

(a) 3-(6-Amino-5-phenyl-pyridin-2-yl)-1-piperidin-1-yl-propenone

1.00 g (4 mmol) 6-Bromo-3-phenyl-2-pyridylamine were dissolved in 100 ml of acetonitrile, 0.22 (1 mmol) of palladium acetate, 0.61 mg of tri(ortho-tolyl)phoshine and 0.89 g (6.4 mmol) of 1-(piperidin-1-yl)-propenone were added, and the mixture was refluxed in a sealed tube for 20 h. After evaporation to dryness, the obtained product was purified by chromatography (silica gel, dichloromethane). Yield: 95 mg.

(b) 3-(6-Amino-5-phenyl-pyridin-2-yl)-1-(piperidin-1-yl)-propanone

65 mg (0.21 mmol) of 3-(6-amino-5-phenyl-pyridin-2-yl)-1-piperidin-1-yl-propenone were dissolved in ethanol and hydrogenated over 10% palladium on carbon at atmospheric pressure and room temperature. After evaporation to dryness, the obtained product was purified by chromatography (silica gel, dichloromethane/methanol 98:2). Yield: 22 mg.

MS: m/e=310 (M+H)⁺

Example 80 3-[4-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

(a) 3-(4-Bromo-thiophen-2-yl)-acrylic acid

25 g (131 mmol) of 4-bromo-thiophene-2-carbaldehyde were dissolved in 180 ml of pyridine, and 16.34 g (157 mmol) of malonic acid and 1.11 g (13.1 mmol) of piperidine were added. The reaction mix was boiled under reflux for 6 h. After cooling to room temperature, the mixture was poured onto a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 21.15 g.

MS: m/e=234 (M+H)⁺

(b) 3-[4-(2-Fluoro-phenyl)-thiophen-2-yl]-1-(piperidin-1-yl)-propan-1-one

The title compound was prepared from 3-(4-bromo-thiophen-2-yl)-acrylic acid analogously as described in Example 15(b) and (c).

MS: m/e=318 (M+H)⁺

Example 81 3-(4-Methyl-2-phenyl-pyrimidin-5-yl)-1-(piperidin-1-yl)-propan-1-one

(a) 3-(4-Methyl-2-phenyl-pyrimidin-5-yl)-acrylic acid

The title compound was prepared from 4-methyl-2-phenyl-pyrimidine-5-carbaldehyde analogously as described in Example 78(a).

MS: m/e=241 (M+H)⁺

(b) 3-(4-Methyl-2-phenyl-pyrimidin-5-yl)-1-(piperidin-1-yl)-propan-1-one

The title compound was prepared from 3-(4-methyl-2-phenyl-pyrimidin-5-yl)-acrylic acid analogously as described in Example 15(b) and (c).

MS: m/e=310 (M+H)⁺

Example 82 3-[5-(4-Fluoro-phenyl)-pyridin-3-yl]-1-piperidin-1-yl-propan-1-one trifluoroacetic acid salt

(a) 3-[5-(4-Fluoro-phenyl)-pyridin-3-yl]-acrylic acid

The title compound was prepared from 5-(4-fluoro-phenyl)-pyridine-3-carbaldehyde analogously as described in Example 78(a).

MS: m/e=244 (M+H)⁺

(b) 3-[5-(4-Fluoro-phenyl)-pyridin-3-yl]-1-piperidin-1-yl-propan-1-one trifluoroacetic acid salt

The title compound was prepared from 3-[5-(4-fluoro-phenyl)-pyridin-3-yl]-acrylic acid analogously as described in Example 15(b) and (c).

MS: m/e=313 (M+H)⁺

Example 83 3-[6-(3-Fluoro-phenyl)-pyridin-3-yl]-1-(piperidin-1-yl)-propan-1-one trifluoroacetic acid salt

(a) 3-(6-Bromo-pyridin-3-yl)-1-(piperidin-1-yl)-propan-1-one

9 g (39 mmol) of 3-(6-bromo-pyridin-3-yl)-propionic acid, 22.5 g (195 mmol) of NEM and 12.83 g (39 mmol) of TOTU were dissolved in 30 ml of DMF and stirred at room temperature for 15 min. 3.33 g (39 mmol) of piperidine were, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated sodium hydrogencarbonate solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 10.2 g.

MS: m/e=298 (M+H)⁺

(b) 3-[6-(3-Fluoro-phenyl)-pyridin-3-yl]-1-(piperidin-1-yl)-propan-1-one trifluoroacetic acid salt

0.100 g (0.34 mmol) of 3-(6-bromo-pyridin-3-yl)-1-piperidin-1-yl-propan-1-one and 57.7 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 3 ml of degassed DME and stirred at room temperature for 10 min. 70 mg (0.5 mmol) of 3-fluoro-phenylboronic acid and 1 ml of an aqueous 2 M sodium carbonate solution were added. The reaction mixture was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration through a pad of silica gel. The pad was washed with dichloromethane, and the resulting solution was evaporated to dryness. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 28 mg.

MS: m/e=313 (M+H)⁺

Example 84 3-(6-Benzo[b]thiophen-2-yl-pyridin-3-yl)-1-(piperidin-1-yl)-propan-1-one trifluoroacetic acid salt

The title compound was prepared from 3-(6-bromo-pyridin-3-yl)-1-(piperidin-1-yl)-propan-1-one and benzo[b]thiophene-2-boronic acid analogously as described in Example 81 (b).

MS: m/e=351 (M+H)⁺

Example 85 2-[6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

(a) [6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-acetic acid tert-butyl ester

Under argon, 300 mg (1.59 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ylamine (prepared analogously as described in Example 76(a) and (b)) and 104 mg (2.39 mmol) of sodium hydride (55% in mineral oil) in DMF were stirred at room temperature for 30 min. Then 466.4 mg (2.39 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 2 h at room temperature and for 5 h at 100° C. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried and evaporated. Yield: 480 mg.

(b) [6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt

480 mg (1.59 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid tert-butyl ester in 5 ml of 90% aqueous TFA were allowed to stand at room temperature overnight. The mixture was concentrated and lyophilized. Yield: 587 mg.

MS: m/e=247 (M+H)⁺

(c) 2-[6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 46.3 mg (0.54 mmol) of piperidine. Yield: 6 mg.

MS: m/e=314 (M+H)⁺

Example 86 2-[6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-1-(pyrrolidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 38.7 mg (0.54 mmol) pyrrolidine. Yield: 4 mg.

MS: m/e=300 (M+H)⁺

Example 87 2-[6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-N-(thiazol-2-yl)-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 54.5 mg (0.54 mmol) 2-aminothiazole. Yield: 2.3 mg.

MS: m/e=329 (M+H)⁺

Example 88 2-[6-(4-Fluoro-phenyl)-pyridin-3-ylamino]-N-(pyridin-3-yl)-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 51.2 mg (0.54 mmol) 3-aminopyridine. Yield: 2.56 mg.

MS: m/e=323 (M+H)⁺

Example 89 2-[6-(2-Fluoro-phenyl)-pyridin-3-ylamino]-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 79 mg (0.21 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 35.7 mg (0.42 mmol) piperidine. Yield: 4.3 mg.

MS: m/e=314 (M+H)⁺

Example 90 2-(5-Phenyl-[1,3,4]thiadiazol-2-ylamino)-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

(a) (5-Phenyl-[1,3,4]thiadiazol-2-ylamino)-acetic acid tert-butyl ester

1 g (5.6 mmol) of 5-phenyl-[1,3,4]thiadiazol-2-ylamine was dissolved in 20 ml of DMF, and 3.1 g (22.6 mmol) of potassium carbonate and 1.1 g (5.6 mmol) of tert-butyl bromoacetate were added. The reaction mixture was stirred at room temperature for 16 h. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the residue. The solution was washed with water, dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 300 mg.

MS: m/e=292 (M+H)⁺

(b) (5-Phenyl-[1,3,4]thiadiazol-2-ylamino)-acetic acid

290 mg (0.99 mmol) of (5-phenyl-[1,3,4]thiadiazol-2-ylamino)-acetic acid tert-butyl ester in 5 ml of TFA and 5 ml of dichloromethane at room temperature for 16 h. The volatiles were removed under reduced pressure.

(c) 2-(5-Phenyl-[1,3,4]thiadiazol-2-ylamino)-1-(piperidin-1-yl)-ethanone trifluoroacetic acid salt

The title compound was prepared from (5-phenyl-[1,3,4]thiadiazol-2-ylamino)-acetic and piperidine acid analogously as described in Example 24(c).

MS: m/e=303 (M+H)⁺

Example 91 2-[4-(4-Chloro-phenyl)-thiazol-2-ylsulfanyl]-1-(pyrrolidin-1-yl)-ethanone

(a) [4-(4-Chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid tert-butyl ester

888.7 mg (8.78 mmol) of triethylamine were added dropwise with caution to a solution of 1000 mg (4.39 mmol) of 4-(4-chloro-phenyl)-thiazole-2-thiol and 856.5 mg (4.39 mmol) of bromoacetic acid tert-butyl ester in 15 ml of DMF. The reaction mixture was stirred at room temperature for 1.5 h. Then water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried and evaporated. Yield: 1.44 g.

MS: m/e=341 (M+H)⁺

(b) [4-(4-Chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid trifluoroacetic acid salt

709 mg (2.07 mmol) of [4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid tert-butyl ester in 5 ml of 90% aqueous TFA were allowed to stand at room temperature for 5 h. The mixture was evaporated. Yield: 665 mg.

MS: m/e=286 (M+H)⁺

(c) 2-[4-(4-Chloro-phenyl)-thiazol-2-ylsulfanyl]-1-(pyrrolidin-1-yl)-ethanone

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.25 mmol) of [4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid trifluoroacetic acid salt and 35.6 mg (0.5 mmol) of pyrrolidine. Yield: 51 mg.

MS: m/e=339 (M+H)⁺

Analogously as described in Example 91 (d), the example compounds of the formula Ig listed in Table 2 were prepared from 100 mg (0.25 mmol) of [4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid trifluoroacetic acid salt and 0.5 mmol) of the respective amine. The compounds may be named as N-substituted 2-[4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-acetamide, for example as 2-[4-(4-chloro-phenyl)-thiazol-2-ylsulfanyl]-N-(thiazol-2-yl)-acetamide in the case of Example 92.

TABLE 2 Example compounds of the formula Ig Example No.

Yield MS: m/e = 92

36 mg 368 (M + H)⁺ 93

28 mg 379 (M + H)⁺ 94

50 mg 379 (M + H)⁺ 95

13 mg 362 (M + H)⁺ 96

54 mg 369 (M + H)⁺ 97

43 mg 341 (M + H)⁺

Example 98 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylsulfanyl]-1-(pyrrolidin-1-yl)-ethanone

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 52.8 mg (0.74 mmol) of pyrrolidine. Yield: 17 mg.

MS: m/e=323 (M+H)⁺

Example 99 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylsulfanyl]-N-(pyridin-2-yl)-acetamide

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 69.9 mg (0.74 mmol) of 2-amino-pyridine. Yield: 20 mg.

MS: m/e=346 (M+H)⁺

Example 100 N-tert-Butyl-2-[4-(4-Fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetamide

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 54.3 mg (0.74 mmol) of tert-butylamine. Yield: 31 mg.

MS: m/e=325 (M+H)⁺

Example 101 2-[4-(4-Fluoro-phenyl)-thiazol-2-ylsulfanyl]-N,N-diisopropyl-acetamide

The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 75.1 mg (0.74 mmol) of diisopropylamine. Yield: 57 mg.

MS: m/e=353 (M+H)⁺

Example 102 2-[6-(4-Fluoro-phenyl)-pyridin-3-yloxy]-N-(pyridin-2-yl)-acetamide trifluoroacetic acid salt

(a) [6-(4-Fluoro-phenyl)-pyridin-3-yloxy]-acetic acid tert-butyl ester

119 mg (2.72 mmol) of sodium hydride (55% in mineral oil) were added to 430 mg (2.27 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ol (prepared analogously as described in Example 76(a) to (d)) in 10 ml of DMF, and the mixture was stirred at room temperature for 60 min. Then 532 mg (2.72 mmol) of bromoacetic acid tert-butyl ester were added, and the reaction mixture was stirred at room temperature for 3 h. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried, and evaporated. Yield: 433 mg.

MS: m/e=304 (M+H)⁺

(b) [6-(4-Fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt

433 mg (1.43 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid tert-butyl ester in 10 ml of 90 aqueous TFA were allowed to stand at room temperature for 1 h. The mixture was concentrated and coevaporated with toluene. Yield: 402 mg.

MS: m/e=248 (M+H)⁺

(c) 2-[6-(4-Fluoro-phenyl)-pyridin-3-yloxy]-N-(pyridin-2-yl)-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 39.5 mg (0.39 mmol) of 2-aminopyridine. Yield: 9.3 mg.

MS: m/e=324 (M+H)⁺

Example 103 N-(4-Fluoro-phenyl)-2-[6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 43.8 mg (0.39 mmol) of 4-fluoroaniline. Yield: 31 mg.

MS: m/e=341 (M+H)⁺

Example 104 N-(2-Fluoro-phenyl)-2-[6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 43.8 mg (0.39 mmol) of 2-fluoroaniline. Yield: 9 mg.

MS: m/e=341 (M+H)⁺

Example 105 2-[6-(4-Fluoro-phenyl)-pyridin-3-yloxy]-N-(thiazol-2-yl)-acetamide trifluoroacetic acid salt

The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 39.5 mg (0.39 mmol) of 2-aminothiazole. Yield: 20 mg.

MS: m/e=330 (M+H)⁺

Example 106 Piperidine-1-carboxylic acid 6-phenoxy-pyridin-3-ylmethyl ester trifluoroacetic acid salt

200 mg (1 mmol) of (6-phenoxy-pyridin-3-yl)-methanol were dissolved in 5 ml of dichloromethane and 1 ml of triethylamine. 147 mg (1 mmol) of piperidine-1-carbonyl chloride were added, and the reaction mixture was heated to 200° C. for 2 h, resulting in evaporation of the solvents. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a white solid. Yield: 120 mg.

MS: m/e=313 (M+H)⁺

The following example compounds of the formulae Ih and Ik listed in Table 3 and Table 4 were prepared analogously to the above examples. The compounds may be named as N-substituted 3-heteroaryl-propionamide, for example as 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-propionamide in the case of Example 114 or N-cyclohexyl-quinolin-3-yl-propionamide in the case of Example 136, or as 1-substituted 3-heteroaryl-propan-1-one, for example as 3-[6-(2,4-difluoro-phenoxy)-pyridin-3-yl]-1-(piperidin-1-yl)-propan-1-one trifluoroacetic acid salt in the case of Example 127, or in another manner, depending on the structure of the individual compound.

TABLE 3 Example compounds of the formula Ih Example No. R³—

MS: m/e = 107

313 (M + H)⁺ 108

331 (M + H)⁺ 109

363 (M + H)⁺ 110

356 (M + H)⁺ 111

396 (M + H)⁺ 112

361 (M + H)⁺ 113

285 (M + H)⁺ 114

327 (M + H)⁺ 115

327 (M + H)⁺ 116 (a)

335 (M + H)⁺ 117 (a)

331 (M + H)⁺ 118 (a)

309 (M + H)⁺ 119 (a)

331 (M + H)⁺ 120 (a)

331 (M + H)⁺ 121 (a)

313 (M + H)⁺ 122 (a)

329 (M + H)⁺ 123 (a)

345 (M + H)⁺ (a) trifluoroacetic acid salt

TABLE 4 Example compounds of the formula Ik Example No. R³—X—Het—

MS: m/e = 124 (a)

296 (M + H)⁺ 125 (b)

329 (M + H)⁺ 126 (b)

329 (M + H)⁺ 127 (b)

347 (M + H)⁺ 128 (b)

409 (M + H)⁺ 129

329 (M + H)⁺ 130

329 (M + H)⁺ 131

269 (M + H)⁺ 132

312 (M + H)⁺ 133

346 (M + H)⁺ 134

348 (M + H)⁺ 135

277 (M + H)⁺ 136

283 (M + H)⁺ 137

313 (M + H)⁺ 138

327 (M + H)⁺ (a) hydrochloride (b) trifluoroacetic acid salt

Determination of the Biological Activity

A) Activation of eNOS Transcription

Activation of eNOS transcription was measured as described in detail by Li et al., “Activation of protein kinase C alpha and/or epsilon enhances transcription of the human endothelial nitric oxide synthase gene”, Mol. Pharmacol. 53 (1998) 630. Briefly, a 3.5 kB long fragment 5′ of the starting codon of the eNOS gene was cloned, sequenced and cloned in firefly luciferase expression plasmids to monitor activation of the eNOS promoter by reporter gene activity. A human endothelial cell line stable transfected and expressing this promoter-reporter construct was used for compound testing. Cells were incubated for 18 h with the compounds.

All compounds were dissolved in sterile dimethyl sulfoxide (DMSO). A final concentration of 0.5% DMSO in complete medium was allowed. Induction of reporter gene expression in these cells was measured using a standard luciferase assay system (Promega, Cat. No. E150) according to the manufacturer's instructions. Luciferase induction in cells incubated with compounds were compared to those incubated with solvent alone. The ratio of both activities (transcription induction ratio, TIR) was plotted as a function of compound concentration. Typically, TIR values started at low concentrations at a ratio of 1, indicating no compound effect, and extended up to a maximum TIR value TIR(max) which indicates the increase of the eNOS transcription. EC₅₀ values of transcription induction ratios as a function of compound concentration were determined graphically.

Numerous compounds of the instant invention were tested by the above-described assay and found to increase protein transcription. Generally, the tested compounds exhibited EC₅₀ values of less than about 50 μM. Preferred compounds, including the compounds of examples 8, 10, 20, 50, 67, 89, 98, 100, 129, for example, exhibited EC₅₀ values of from about 5 μM to about 0.5 μM. More preferred compounds, including the compounds of examples 7, 69, 77, 78, 79, for example, exhibited EC₅₀ values of less than about 0.5 μM.

The effect of compounds on eNOS-transcription was confirmed in a second assay based on eNOS protein detection. Primary human umbilical vein cord endothelial cells (HUVEC) were isolated and cultivated according to standard procedures. Confluent cells were incubated with compounds for 18 h and the effect on eNOS protein expression determined by a quantitative Western blotting procedure. After compound incubation, HUVEC were lysed in ice-cold lysis buffer containing 10 mM Tris-HCl, pH 8.0, 1% SDS and protease inhibitors. The lysate was subjected to a standard denaturating polyacrylamide gel electrophoresis and blotted to nitrocellulose membranes. Using a specific primary monoclonal antibody (Transduction Laboratories, UK) and alkaline phosphatase labelled secondary antibody (Jackson Labs), a specific eNOS protein band was visualized and quantified based on a chemofluorescence detection method.

The effect of the compounds of the formulae I and Ia can also be investigated in the following animal models (animal experiments are performed in accordance with the German animal protection law and the guidelines for the use of experimental animals as given by the Guide for the Care and Use of Laboratory Animals of the US National Institutes of Health).

Animals and Treatment (Experiments B-D)

ApoE and eNOS deficient mice (C57BL/6J background, Jackson Laboratory, Bar Harbor, Me.) are used. All animals are 10 to 12 weeks of age and weigh 22 to 28 g. Three days before surgery mice are divided into 4 groups (apoE control, n=10 to 12; apoE with test compounds, n=10 to 12; eNOS control, n=10 to 12; eNOS with test compounds, n=10 to 12) and receive either a standard rodent chow (containing 4% of fat and 0.001% of cholesterol; in the following designated as placebo group) or a standard rodent chow+test compound (10 or 30 mg/kg/day p.o.).

B) Anti-Hypertensive Effect in ApoE Knockout Mice

Blood-pressure is determined in conscious mice using a computerized tail-cuff system (Visitech Systems, Apex, Nc). After treatment of ApoE deficient mice and eNOS deficient mice with the test compounds the blood pressure is compared to the results obtained with a placebo treatment.

C) Inhibition of Neointima Formation and Atherogenesis (Femoral Artery Cuff)

After 3 day treatment of ApoE deficient mice with the respective compound (10 mg/kg/day pressed in chow), animals are anesthetized with an intraperitoneal injection of pentobarbital (60 mg/kg) followed by an intramuscular injection of xylazin (2 mg/kg) and a cuff is placed around the femoral artery as described in Moroi et al. (J Clin. Invest. 101 (1998) 1225). Briefly, the left femoral artery is dissected. A non-occlusive 2.0 mm polyethylene cuff made of PE 50 tubing (inner diameter 0.56 mm, outer diameter 0.965 mm, Becton Dickinson, Mountain View, Calif.) is placed around the artery and tied in place with two 7-0 sutures. The right femoral artery is isolated from the surrounding tissues but a cuff is not placed. Treatment with the respective compound is continued for 14 days after surgery. Then the animals are sacrificed. The aorta are taken for determination of vascular eNOS expressions by quantitative western blotting. Both femoral arteries are harvested, fixed in formalin and embedded in paraffin. 20 cross sections (10 μm) are cut from the cuffed portion of the left femoral artery and from the corresponding segment of the right artery. Sections are subjected to standard hematoxylin and eosin staining. Morphometric analyses are performed using an image analysis computer program (LeicaQWin, Leica Imaging Systems, Cambridge, GB). For each cross section the area of the lumen, the neointima and the media are determined. To this end, the neointima is defined as the area between the lumen and the internal elastic lamina and the media is defined as the area between the internal and the external elastic lamina. The ratio between the area of the neointima and the area of the media is expressed as the neointima/media ratio. The results obtained in the compound group are compared to those obtained in the placebo group.

D) Prevention of Atherosclerotic Plaque Formation in Chronic Treatment

ApoE deficient mice are treated for 16 weeks with the respective compound pressed in chow and finally sacrificed. Aortas are removed from each mouse, fixed in formalin and embedded in paraffin. Plaque formation is measured via lipid lesions formation in the aortas (from aortic arch to diaphragm) and is analyzed by oil red 0 staining. For quantifying the effect of the respective compound on vascular eNOS expression the femoral arteries are used in this experiment. The results obtained in the compound group are compared to those obtained in the placebo group.

E) Improvement of Coronary Function in Diseased ApoE Deficient mice

Old Male wild-type C57BL/6J mice (Charles River Wiga GmbH, Sulzfeld), and apoE deficient mice (C57BL/6J background, Jackson Laboratory, Bar Harbor, Me.) of 6 month of age and weighing 28 to 36 g are used in the experiments. Mice are divided into 3 groups (C57BL/6J, n=8; apoE control, n=8; apoE with respective compound, n=8) and receive for 8 weeks either a standard rodent chow (containing 4% of fat and 0.001% of cholesterol) or a standard rodent chow+respective compound (30 mg/kg/day p.o.). Mice are anesthetized with sodium pentobarbitone (100 mg/kg i.p.), and the hearts are rapidly excised and placed into ice-cold perfusion buffer. The aorta is cannulated and connected to a perfusion apparatus (Hugo Sachs Electronics, Freiburg, Germany) which is started immediately at a constant perfusion pressure of 60 mm Hg. Hearts are perfused in a retrograde fashion with modified Krebs bicarbonate buffer, equilibrated with 95% O₂ and 5% CO₂ and maintained at 37.5° C. A beveled small tube (PE 50) is passed through a pulmonary vein into the left ventricle and pulled through the ventricular wall, anchored in the apex by a fluted end, and connected to a tip-micromanometer (Millar 1.4 French). The left atrium is cannulated through the same pulmonary vein and the heart switched to the working mode with a constant preload pressure of 10 mm Hg and an afterload pressure of 60 mm Hg. Aortic outflow and atrial inflow are continuously measured using ultrasonic flow probes (HSE/Transonic Systems Inc.). Coronary flow is calculated as the difference between atrial flow and aortic flow. All hemodynamic data are digitized at a sampling rate of 1000 Hz and recorded with a PC using spezialized software (HEM, Notocord).

Hearts are allowed to stabilize for 30 min. All functional hemodynamic data are measured during steady state, and during volume and pressure loading. Left ventricular function curves are constructed by varying pre-load pressure. For acquisition of preload curves, afterload is set at 60 mm Hg and preload is adjusted in 5 mm Hg steps over a range of 5 to 25 mm Hg. Hearts are allowed to stabilize at baseline conditions between pressure and volume loading. 

1. A compound of the formula I,

in which A is chosen from CH₂—CH₂, CH₂—CH₂—CH₂, Y—CH₂, CH₂—Y, Y—CH₂—CH₂ and CH₂—CH₂—Y, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ or Y—CH₂—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered or 6-membered, monocyclic aromatic group which contains one or two identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond, CH₂, O and NH, provided that X cannot be O or NH if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from (C₁-C₄)-alkyl and fluorine; R^(b) is chosen from hydrogen, (C₁-C₄)-alkyl and (C₁-C₄)-alkyl-CO—; R¹ and R² are independently of each other chosen from hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl, (C₃-C₆)-alkynyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, but cannot simultaneously be hydrogen, wherein the groups (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, (C₃-C₆)-alkenyl and (C₃-C₆)-alkynyl can all be substituted by one or more identical or different substituents R⁶, and the groups C_(n)H_(2n) can all be substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl, and all phenyl and heteroaryl groups can independently of each other be substituted on carbon atoms by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring members chosen from N, NR⁹, O, S, SO and SO₂ which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted on ring carbon atoms by one or more identical or different substituents R⁸; R³ is chosen from phenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, H₂NSO₂— and (C₁-C₄)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; R⁶ is chosen from fluorine, OH, oxo, (C₁-C₄)-alkyloxy, (C₁-C₄)-alkylmercapto, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁷ is chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, SF₅, H₂NSO₂— and (C₁-C₄)-alkyl-SO₂—; R⁸ is chosen from fluorine, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, OH, oxo, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy, (C₁-C₄)-alkylmercapto, NH₂, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, ((C₁-C₄)-alkyl)-CONH—, di((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyl)aminocarbonyl-, ((C₁-C₄)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁹ is chosen from hydrogen, (C₁-C₄)-alkyl, ((C₁-C₄)-alkyl)-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, CF₃ and (C₁-C₄)-alkyloxy; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered or 6-membered, monocyclic aromatic group which contains one, two or three identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; and n is 0, 1 or 2, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof; provided that the group R³—X-Het cannot be 4-phenyl-thiazol-2-yl if simultaneously the group A-CO—NR¹R² is the group O—CH₂—CO—N(CH₃)-phenyl, the group S—CH₂—CO—NH—CH₂—CH₂—OH, the group CH₂—NH—CO—NH-phenyl, the group NH—CH₂—CO—N(CH₃)₂, or the group NH—CH₂—CO—NH—R⁹⁰ in which R⁹⁰ is phenyl, 3-chloro-phenyl, 4-chloro-phenyl or 3-chloro-4-fluoro-phenyl; and provided that the group R³—X-Het cannot be 4-(4-chloro-phenyl)-thiazol-2-yl if simultaneously the group A-CO—NR¹R² is the group S—CH₂—CO—NH—R⁹¹ in which R⁹¹ is phenyl, 4-bromo-phenyl, 4-chloro-phenyl, 4-methoxy-phenyl or 4-methyl-phenyl; and provided that the group R³—X-Het cannot be 3-phenyl-isoxazol-5-yl, 3-ethyl-4-phenyl-isoxazol-5-yl, 5-phenyl-isoxazol-3-yl or 4-chloro-5-(3,4-dichloro-phenyl)-thiazol-2-yl if simultaneously the group A-CO—NR¹R² is the group O—CH₂—CO—N(CH₃)— phenyl; and provided that the group R³—X-Het cannot be a pyrrol-2-yl group which is substituted by ethoxycarbonyl in the 3-position and by phenyl, 4-chloro-phenyl or 4-bromophenyl in the 4-position, if simultaneously the group A-CO—NR¹R² is the group S—CH₂—CO—NH—R⁹² in which R⁹² is benzyl, 3,4-dimethoxy-benzyl or 2-(4-methoxy-phenyl)-ethyl; and provided that the compound of the formula I cannot be N-benzyl-3-[4-(4-chloro-phenyl)-oxazol-2-yl]-N-methyl-propionamide, 3-[4-(4-chloro-phenyl)-oxazol-2-yl]-N-methyl-propionamide, N,N-diethyl-3-[4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-thiazol-2-yl]-propionamide, 2-(4-chloro-5-phenyl-thiazol-2-yloxy)-1-(2-methyl-piperidin-1-yl)-ethanone, (4-methyl-phenyl)-carbamic acid 4-(3-amino-4-methoxy-phenyl)-thiazol-2-ylmethyl ester or N-(4-chloro-phenyl)-2-(4-phenyl-1H-imidazol-2-ylsulfanyl)-acetamide.
 2. A compound as claimed in claim 1, in which Het is chosen from pyridinediyl, thiazolediyl and thiophenediyl, which can all be substituted on ring carbon atoms by one or more identical or different substituents R⁵; or a physiologically acceptable salt thereof.
 3. A compound as claimed in claim 2, in which Het is chosen from pyridinediyl and thiophenediyl, which can all be substituted on ring carbon atoms by one or more identical or different substituents R⁵; or a physiologically acceptable salt thereof.
 4. A compound as claimed in claim 1, in which Het is a 6-membered monocyclic aromatic group which contains one or two ring nitrogen atoms and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; or a physiologically acceptable salt thereof.
 5. A compound as claimed in claim 3, in which Het is pyridinediyl which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; or a physiologically acceptable salt thereof.
 6. A compound as claimed in claim 1, in which A is chosen from CH₂—CH₂ and Y—CH₂; or a physiologically acceptable salt thereof.
 7. A compound as claimed in claim 1, in which X is chosen from a direct bond and O; or a physiologically acceptable salt thereof.
 8. A compound as claimed in claim 1, in which R¹ is chosen from (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, and R² is chosen from hydrogen and (C₁-C₄)-alkyl, wherein all (C₁-C₄)-alkyl and (C₃-C₇)-cycloalkyl groups can be substituted by one or more identical or different substituents R⁶, and all phenyl and heteroaryl groups can be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 7-membered monocyclic, saturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one further heteroatom ring member chosen from NR⁹, O, S, SO and SO₂, wherein the ring formed by R¹ and R² and the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸; or a physiologically acceptable salt thereof.
 9. A compound as claimed in claim 1, in which R³ is phenyl which can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy-(C₁-C₂)-alkyl-, (C₁-C₄)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₄)-alkylmercapto, (C₁-C₄)-alkylamino, di((C₁-C₄)-alkyl)amino, CONH₂, CN, CF₃ and (C₁-C₄)-alkyl-SO₂—; or a physiologically acceptable salt thereof.
 10. A process for the preparation of a compound as claimed in claim 1, or a physiologically acceptable salt thereof, comprising reacting a compound of the formula IV and a compound of the formula V,

wherein Het, A, X, R¹, R² and R³ are defined as in claim 1 and, in addition, any functional groups can be present in protected form or in the form of precursor groups, and R is hydrogen, (C₁-C₄)-alkyl or benzyl.
 11. A pharmaceutical composition, comprising at least one compound as claimed in claim 1, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 12. A method of treating a patient for a condition which responds to the stimulation of the expression of endothelial NO synthase, the method comprising administering to the patient a pharmaceutically effective dose of a compound of the formula Ia,

in which A is chosen from CH₂—CH₂, CH₂—CH₂—CH₂, Y—CH₂, CH₂—Y, Y—CH₂—CH₂ and CH₂—CH₂—Y, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ or Y—CH₂—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered to 10-membered, monocyclic or bicyclic, aromatic group which contains one or more identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond, CH₂, O, CH₂—O, O—CH₂, S, NH and N((C₁-C₄)-alkyl), or X is absent and in this case the phenyl, naphthalenyl or heteroaryl group representing the group R³ is fused to the group Het, provided that X cannot be O, CH₂—O, S, NH or N((C₁-C₄)-alkyl) if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from (C₁-C₆)-alkyl, fluorine and oxo; R^(b) is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₆)-alkyl, CF₃ and (C₁-C₆)-alkyloxy; R¹ and R² are independently of each other chosen from hydrogen, (C₁-C₁₀)-alkyl, (C₃-C₁₀)-alkenyl, (C₃-C₁₀)-alkynyl, (C₃-C₁₀)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)—, naphthalenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, wherein the groups (C₁-C₁₀)-alkyl, (C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-alkenyl and (C₃-C₁₀)-alkynyl can all be substituted by one or more identical or different substituents R⁶, and the groups C_(n)H_(2n) can all be substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl, and all phenyl, naphthalenyl and heteroaryl groups can independently of each other be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring members chosen from N, NR⁹, O, S, SO and SO₂ which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸; R³ is chosen from phenyl, naphthalenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, COOH, CONH₂, CN, CF₃, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂—, H₂NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, COOH, CONH₂, CN, CF₃, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁶ is chosen from fluorine, OH, oxo, (C₁-C₆)-alkyloxy, (C₁-C₆)-alkylmercapto, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁷ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, SF₅, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁸ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, oxo, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁹ is chosen from hydrogen, (C₁-C₆)-alkyl, ((C₁-C₆)-alkyl)-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, CF₃ and (C₁-C₄)-alkyloxy; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered to 10-membered, monocyclic or bicyclic aromatic group which contains one or more identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; and n is 0, 1, 2 or 3, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof.
 13. A method of treating a patient for a condition selected from stable or unstable angina pectoris, coronary heart disease, coronary artery disease, Prinzmetal angina, acute coronary syndrome, cardiac insufficiency, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, restenosis, endothel damage after PTCA, hypertension, essential hypertension, pulmonary hypertension, secondary hypertension, renovascular hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes, diabetes complications, nephropathy, retinopathy, angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance or a restricted ability to learn, or for the lowering of cardiovascular risk of postmenopausal women or after intake of contraceptives, the method comprising administering to the patient a pharmaceutically effective dose of a compound of the formula Ia,

in which A is chosen from CH₂—CH₂, CH₂—CH₂—CH₂, Y—CH₂, CH₂—Y, Y—CH₂—CH₂ and CH₂—CH₂—Y, wherein all CH₂ groups can be substituted by one or more identical or different substituents R^(a), provided that A cannot be Y—CH₂ or Y—CH₂—CH₂ if the group A is bonded to a ring nitrogen atom of the group Het; Het is a 5-membered to 10-membered, monocyclic or bicyclic, aromatic group which contains one or more identical or different heteroatom ring members chosen from N, NR⁴, O and S, and which can be substituted on ring carbon atoms by one or more identical or different substituents R⁵; X is chosen from a direct bond, CH₂, O, CH₂—O, O—CH₂, S, NH and N((C₁-C₄)-alkyl), or X is absent and in this case the phenyl, naphthalenyl or heteroaryl group representing the group R³ is fused to the group Het, provided that X cannot be O, CH₂—O, S, NH or N((C₁-C₄)-alkyl) if the group R³—X— is bonded to a ring nitrogen atom of the group Het; Y is chosen from O, S and NR^(b); R^(a) is chosen from (C₁-C₆)-alkyl, fluorine and oxo; R^(b) is chosen from hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₆)-alkyl, CF₃ and (C₁-C₆)-alkyloxy; R¹ and R² are independently of each other chosen from hydrogen, (C₁-C₁₀)-alkyl, (C₃-C₁₀)-alkenyl, (C₃-C₁₀)-alkynyl, (C₃-C₁₀)-cycloalkyl-C_(n)H_(2n)—, phenyl-C_(n)H_(2n)—, naphthalenyl-C_(n)H_(2n)— and heteroaryl-C_(n)H_(2n)—, wherein the groups (C₁-C₁₀)-alkyl, (C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-alkenyl and (C₃-C₁₀)-alkynyl can all be substituted by one or more identical or different substituents R⁶, and the groups C_(n)H_(2n) can all be substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl, and all phenyl, naphthalenyl and heteroaryl groups can independently of each other be substituted by one or more identical or different substituents R⁷, or R¹ and R², together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated or unsaturated ring which, in addition to the ring nitrogen atom carrying R¹ and R², can contain one or two further heteroatom ring members chosen from N, NR⁹, O, S, SO and SO₂ which can be identical or different, with the proviso that two ring members from the series O, S, SO and SO₂ cannot be present in adjacent ring positions, wherein the ring formed by R¹ and R² together with the nitrogen atom carrying them can be substituted by one or more identical or different substituents R⁸; R³ is chosen from phenyl, naphthalenyl and heteroaryl which can all be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, COOH, CONH₂, CN, CF₃, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂—, H₂NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁴ is chosen from hydrogen and (C₁-C₄)-alkyl; R⁵ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, COOH, CONH₂, CN, CF₃, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁶ is chosen from fluorine, OH, oxo, (C₁-C₆)-alkyloxy, (C₁-C₆)-alkylmercapto, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN and CF₃; R⁷ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, SF₅, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁸ is chosen from halogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkyloxy-(C₁-C₃)-alkyl-, OH, oxo, (C₁-C₆)-alkyloxy which can be substituted by one or more fluorine atoms, (C₁-C₃)-alkylenedioxy which can be substituted by one or more fluorine atoms, (C₁-C₆)-alkylmercapto, NH₂, (C₁-C₆)-alkylamino, di((C₁-C₆)-alkyl)amino, ((C₁-C₆)-alkyl)-CONH—, ((C₁-C₆)-alkyl)-SO₂NH—, di((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyl)aminocarbonyl-, ((C₁-C₆)-alkyloxy)carbonyl-, CONH₂, CN, CF₃, H₂NSO₂—, ((C₁-C₆)-alkyl)NHSO₂—, di((C₁-C₆)-alkyl)NSO₂— and (C₁-C₆)-alkyl-SO₂—; R⁹ is chosen from hydrogen, (C₁-C₆)-alkyl, ((C₁-C₆)-alkyl)-CO— and phenyl-CO—, wherein the phenyl group can be substituted by one or more identical or different substituents chosen from halogen, (C₁-C₄)-alkyl, CF₃ and (C₁-C₄)-alkyloxy; R¹⁰ is chosen from hydrogen and (C₁-C₄)-alkyl; heteroaryl is a 5-membered to 10-membered, monocyclic or bicyclic aromatic group which contains one or more identical or different heteroatom ring members chosen from N, NR¹⁰, O and S; and n is 0, 1, 2 or 3, where all numbers n are independent of each other and can be identical or different; in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof.
 14. A method of treating a patient for a condition which responds to the stimulation of the expression of endothelial NO synthase, the method comprising administering to the patient a pharmaceutically effective dose of a compound of the formula I as defined in claim 1, or a physiologically acceptable salt thereof.
 15. A method of treating a patient for a condition selected from stable or unstable angina pectoris, coronary heart disease, coronary artery disease, Prinzmetal angina, acute coronary syndrome, cardiac insufficiency, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, restenosis, endothelial damage after PTCA, hypertension, essential hypertension, pulmonary hypertension, secondary hypertension, renovascular hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes, diabetes complications, nephropathy, retinopathy, angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance or a restricted ability to learn, or for the lowering of cardiovascular risk of postmenopausal women or after intake of contraceptives, the method comprising administering to the patient a pharmaceutically effective dose of a compound of the formula I as defined in claim 1, or a physiologically acceptable salt thereof. 